Assessment of the correlations of lacosamide concentrations in saliva and serum in patients with epilepsy

Summary

Therapeutic drug monitoring of antiepileptic drugs is based on patient serum samples. In this study, we evaluated the correlation between lacosamide (LCM) steady state concentrations in serum and saliva samples. Additionally, we investigated the relation with daily dose, and assessed the feasibility of saliva collection. This was an open-label, single center study including data from 25 patients at the Bethel Epilepsy Center treated with LCM (50-650 mg/d). Samples were collected in the morning (fasting values) and in selected cases at 50 minutes to 5 hours after the morning dose. Nonsignificant differences in the mean LCM morning (trough) concentration in serum and saliva were observed. Serum and saliva concentrations across all samples were highly correlated, (r = .874), with a slightly lower correlation when only fasting values were analyzed (r = .860). Higher correlation with daily dosages was observed in serum samples (r = .773) than in saliva samples (r = .604). Serum and saliva concentrations increased significantly after intake of the LCM morning dose (P < .001). The median absolute and percentage increase of LCM in serum were moderately lower than in saliva samples, with a few outliers in saliva samples. Consequently, saliva could offer great clinical potential to monitor drug concentrations and guide LCM treatment in epileptic patients.

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Efficacy and safety of eslicarbazepine acetate monotherapy in patients converting from carbamazepine

Summary

Objective

To evaluate the influence of prior use of carbamazepine (CBZ) and other antiepileptic drugs (AEDs) with a putatively similar mechanism of action (inhibition of voltage-gated sodium channels; VGSCs) on seizure outcomes and tolerability when converting to eslicarbazepine acetate (ESL), using data pooled from 2 controlled conversion-to-ESL monotherapy trials (studies: 093-045, 093-046).

Methods

Adults with treatment-resistant focal (partial-onset) seizures were randomized 2:1 to ESL 1600 or 1200 mg once daily. The primary efficacy endpoint was study exit (meeting predefined exit criteria related to worsening seizure control) versus an historical control group. Other endpoints included change in seizure frequency, responder rate, and tolerability. Endpoints were analyzed for subgroups of patients who received CBZ (or any VGSC inhibitor [VGSCi]) during baseline versus those who received other AEDs.

Results

Of 365 patients in the studies, 332 were evaluable for efficacy. The higher risk of study exit in the subgroups that received CBZ (or any VGSCi) during baseline, versus other AEDs, was not statistically significant (hazard ratios were 1.49 for +CBZ vs −CBZ [P = .10] and 1.27 for +VGSCi vs. −VGSCi [P = .33]). Reductions in seizure frequency and responder rates were lower in patients who converted from CBZ or other VGSCi compared with those who converted from other AEDs. There were no notable differences in overall tolerability between subgroups, but the incidence of some adverse events (eg, dizziness, somnolence, nausea) differed between subgroups and/or between treatment periods.

Significance

Baseline use of CBZ or other major putative VGSC inhibitors did not appear to significantly increase the risk of study exit due to worsening seizure control, or to increase the frequency of side effects when converting to ESL monotherapy. However, bigger improvements in efficacy may be possible in patients converting to ESL monotherapy from an AED regimen that does not include a VGSC inhibitor.

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Protocol investigating the clinical utility of an objective measure of attention, impulsivity and activity (QbTest) for optimising medication management in children and young people with ADHD 'QbTest Utility for Optimising Treatment in ADHD (QUOTA): a feasibility randomised controlled trial

Introduction

Attention-deficit hyperactivity disorder (ADHD) is characterised by symptoms of inattention, hyperactivity and impulsivity. To improve outcomes, the National Institute for Health and Care Excellence ADHD guidelines recommend regular monitoring of symptoms when children commence medication. However, research suggests that routine monitoring rarely happens, and clinicians often rely on subjective information such as reports from parents and teachers to ascertain improvement. These sources can be unreliable and difficult to obtain. The addition of an objective test of attention and activity (QbTest) may improve the objectivity, reliability and speed of clinical decision-making and so reduce the time to identify the optimal medication dose. This study aims to assess the feasibility and acceptability of a QbTest medication management protocol delivered in routine healthcare services for children with ADHD.

Method and analysis

This multisite feasibility randomised controlled trial (RCT) will recruit 60 young people (aged 6–17 years old), diagnosed with ADHD, and starting stimulant medication who are seen by Child and Adolescent Mental Health Services or Community Paediatric services. Participants will be randomised into one of two arms. In the experimental arm (QbTest protocol), the participant will complete a QbTest at baseline (prior to medication initiation), and two follow-up QbTests on medication (2–4 weeks and 8–10 weeks later). In the control arm, participants will receive treatment as usual, with at least two follow-up consultations. Measures of parent-, teacher- and clinician-rated symptoms and global functioning will be completed at each time point. Health economic measures will be completed. Clinicians will record treatment decision-making. Acceptability and feasibility of the protocol will be assessed alongside outcome measure completion rates. Qualitative interviews will be conducted.

Ethics and dissemination

The findings will be used to inform the development of a fully powered RCT. The results will be submitted for publication in peer-reviewed journals. The study has ethical approval.

Trial registration number

NCT03368573; Pre-results.

http://ift.tt/2C1B8TR

MACF1 Overexpression by Transfecting the 21 kbp Large Plasmid PEGFP-C1A-ACF7 Promotes Osteoblast Differentiation and Bone Formation

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 259-270.


http://ift.tt/2C4bCNO

Considerations for Clinical Review of Cellular Therapy Products: Perspectives of the China Food and Drug Administration Center for Drug Evaluation

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 121-127.


http://ift.tt/2suryFc

In Vivo Ovarian Cancer Gene Therapy Using CRISPR-Cas9

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 223-233.


http://ift.tt/2C2ZUDd

National Rare Diseases Registry System of China and Related Cohort Studies: Vision and Roadmap

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 128-135.


http://ift.tt/2sxR8ZZ

Recent Progress on Genetic Diagnosis and Therapy for β-Thalassemia in China and Around the World

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 197-203.


http://ift.tt/2o3zOaO

Recent Advances in Therapeutic Genome Editing in China

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 136-145.


http://ift.tt/2BxED3x

Treatment of Uterine Sarcoma with rAd-p53 (Gendicine) Followed by Chemotherapy: Clinical Study of TP53 Gene Therapy

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 242-250.


http://ift.tt/2C11JAE

Gene Therapy for Hemophilia and Duchenne Muscular Dystrophy in China

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 146-150.


http://ift.tt/2sxR4JJ

Current Status of Nonviral Vectors for Gene Therapy in China

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 110-120.


http://ift.tt/2o0cj2k

Fighting Cancer with Viruses: Oncolytic Virus Therapy in China

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 151-159.


http://ift.tt/2szMoD1

The First Approved Gene Therapy Product for Cancer Ad-p53 (Gendicine): 12 Years in the Clinic

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 160-179.


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Applications of Virus Vector–Mediated Gene Therapy in China

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 98-109.


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Double-Dose Adenovirus-Mediated Adjuvant Gene Therapy Improves Liver Transplantation Outcomes in Patients with Advanced Hepatocellular Carcinoma

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 251-258.


http://ift.tt/2C2B9qY

Stem-Cell Therapy Advances in China

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 188-196.


http://ift.tt/2szCdys

Gene and Cell Therapy in China: Highlighting Excellence in the 21st Century 中国的基因与细胞治疗： 21世纪的飞跃发展和重要贡献

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 97-97.


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Development of Gene Therapeutics for Head and Neck Cancer in China: From Bench to Bedside

Human Gene Therapy Feb 2018, Vol. 29, No. 2: 180-187.


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Cancers, Vol. 10, Pages 52: The Epithelial-to-Mesenchymal Transition in Cancer

Cancers, Vol. 10, Pages 52: The Epithelial-to-Mesenchymal Transition in Cancer

Cancers doi: 10.3390/cancers10020052

Authors: Joëlle Roche

The epithelial-to-mesenchymal transition (EMT) occurs during normal embryonic development, tissue regeneration, organ fibrosis, and wound healing.[...]

http://ift.tt/2sxfhjz

Face cooling reveals a relative inability to increase cardiac parasympathetic activation during passive heat stress

Abstract

We tested the hypothesis that passive heat stress attenuates the increase in cardiac parasympathetic stimulation, vascular resistance, and blood pressure evoked by face cooling. During normothermia and when intestinal temperature was elevated by 1.0 ± 0.2°C, eleven healthy young adults underwent 3 min of face cooling. Face cooling was accomplished by placing a 2.5 L bag of ice water (0 ± 0°C) over the cheeks, eyes, and forehead. Primary variables included forehead skin temperature, mean arterial pressure, and systemic, forearm and cutaneous vascular resistances. Indices of heart rate variability in the time domain provided an index of cardiac parasympathetic activity. The magnitude of reductions in forehead skin temperature during face cooling was slightly greater during normothermia (−17.6 ± 1.9°C vs. −16.3 ± 3.0°C, P = 0.03). Increases in heart rate variability evoked by face cooling were attenuated during heat stress. Changes in systemic, forearm, and cutaneous vascular resistances during face cooling were virtually abolished lower during heat stress (P < 0.01). However, when forearm and vascular data were reported as conductance, differences between normothermia and heat stress were not apparent (P ≥ 0.62). Nevertheless, the increase in mean arterial pressure was attenuated during heat stress with face cooling (at 3 min: 2 ± 7 mmHg) compared to normothermia (at 3 min: 19 ± 7 mmHg, P < 0.01). These data indicate that passive heat stress attenuates face cooling evoked increases in cardiac parasympathetic activation, vascular resistance, and blood pressure. However, they also indicate that changes in indices of vascular resistance do not always reflect equivalent changes in conductance.

This article is protected by copyright. All rights reserved

http://ift.tt/2CnAmMU

Cancers, Vol. 10, Pages 51: Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners

Cancers, Vol. 10, Pages 51: Next Generation Immunotherapy for Pancreatic Cancer: DNA Vaccination is Seeking New Combo Partners

Cancers doi: 10.3390/cancers10020051

Authors: Paola Cappello Claudia Curcio Giorgia Mandili Cecilia Roux Sara Bulfamante Francesco Novelli

Pancreatic Ductal Adenocarcinoma (PDA) is an almost incurable radio- and chemo-resistant tumor, and its microenvironment is characterized by a strong desmoplastic reaction associated with a significant infiltration of T regulatory lymphocytes and myeloid-derived suppressor cells (Tregs, MDSC). Investigating immunological targets has identified a number of metabolic and cytoskeletal related molecules, which are typically recognized by circulating antibodies. Among these molecules we have investigated alpha-enolase (ENO1), a glycolytic enzyme that also acts a plasminogen receptor. ENO1 is also recognized by T cells in PDA patients, so we developed a DNA vaccine that targets ENO1. This efficiently induces many immunological processes (antibody formation and complement-dependent cytotoxicity (CDC)-mediated tumor killing, infiltration of effector T cells, reduction of infiltration of myeloid and Treg suppressor cells), which significantly increase the survival of genetically engineered mice that spontaneously develop pancreatic cancer. Although promising, the ENO1 DNA vaccine does not completely eradicate the tumor, which, after an initial growth inhibition, returns to proliferate again, especially when Tregs and MDSC ensue in the tumor mass. This led us to develop possible strategies for combinatorial treatments aimed to broaden and sustain the antitumor immune response elicited by DNA vaccination. Based on the data we have obtained in recent years, this review will discuss the biological bases of possible combinatorial treatments (chemotherapy, PI3K inhibitors, tumor-associated macrophages, ENO1 inhibitors) that could be effective in amplifying the response induced by the immune vaccination in PDA.

http://ift.tt/2BwnFT7

Targeted therapies for targeted populations: Anti-EGFR treatment for EGFR amplified gastroesophageal adenocarcinoma [Research Articles]

Previous anti-EGFR trials in unselected gastroesophageal adenocarcinoma (GEA) patients were resoundingly negative. We identified EGFR amplification in 5% (19/363) of patients at the University of Chicago, including 6% (8/140) who were prospectively screened with intention-to-treat using anti-EGFR therapy. Seven pts received >1 dose of treatment: three first line FOLFOX plus ABT-806, one second line FOLFIRI plus cetuximab, and three third/fourth line cetuximab alone. Treatment achieved objective response in 58% (4/7) and disease control in 100% (7/7) with a median progression-free survival of 10 months. Pre and post-treatment tumor NGS, serial plasma ctDNA NGS, and tumor IHC/FISH for EGFR revealed pre-existing and/or acquired genomic events including EGFR negative clones, PTEN deletion, KRAS amplification/mutation, NRAS, MYC and HER2 amplification, and GNAS mutations serving as mechanisms of resistance. Two evaluable patients demonstrated interval increase of CD3+ infiltrate, including one who demonstrated increased NKp46+, and PD-L1 IHC expression from baseline, suggesting an immune therapeutic mechanism of action. EGFR amplification predicted benefit from anti-EGFR therapy, albeit until various resistance mechanisms emerged.

http://ift.tt/2GiwJu1

Comment on ‘Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis’

Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis'

Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis', Published online: 15 February 2018; doi:10.1038/bjc.2017.482

Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis'

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Reply to ‘Comment on ‘Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis”

Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis"

Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis", Published online: 15 February 2018; doi:10.1038/bjc.2017.491

Reply to 'Comment on 'Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis"

http://ift.tt/2Hitt32

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients, Published online: 15 February 2018; doi:10.1038/bjc.2017.492

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

http://ift.tt/2GiCJDc

The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia

The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia

The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia, Published online: 15 February 2018; doi:10.1038/bjc.2017.457

The Improving Rural Cancer Outcomes Trial: a cluster-randomised controlled trial of a complex intervention to reduce time to diagnosis in rural cancer patients in Western Australia

http://ift.tt/2HfYy7D

Single-cell transcriptome analyses reveal endothelial cell heterogeneity in tumors and changes following anti-angiogenic treatment

Angiogenesis involves dynamic interactions between specialized endothelial tip and stalk cells that are believed to be regulated in part by VEGF and Dll4-Notch signaling. However, our understanding of this process is hampered by limited knowledge of the heterogeneity of endothelial cells and the role of different signaling pathways in specifying endothelial phenotypes. Here we characterized by single cell transcriptomics the heterogeneity of mouse endothelial cells and other stromal cells during active angiogenesis in xenograft tumors as well as from adult normal heart, following pharmacologic inhibition of VEGF and Dll4-Notch signaling. We classified tumor endothelial cells into three subpopulations that appeared to correspond with tip-like, transition and stalk-like cells. Previously identified markers for tip and stalk cells were confirmed and several novel ones discovered. Blockade of VEGF rapidly inhibited cell cycle genes and strongly reduced the proportion of endothelial tip cells in tumors. In contrast, blockade of Dll4 promoted endothelial proliferation as well as tip cell markers; blockade of both pathways inhibited endothelial proliferation but preserved some tip cells. We also phenotypically classified other tumor stromal cells and found that tumor-associated fibroblasts (TAFs) responded to anti-angiogenic drug treatments by upregulating hypoxia-associated genes and producing secreted factors involved in angiogenesis. Overall, our findings better define the heterogeneity of tumor endothelial and other stromal cells and reveal the roles of VEGF and Dll4-Notch in specifying tumor endothelial phenotype, highlighting the response of stromal cells to anti-angiogenic therapies.

http://ift.tt/2GfeTrW

Exam 1: Health-related Quality of Life and Costs Associated With Eosinophilic Esophagitis: A Systematic Review

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Transcriptional and epigenetic regulation of innate-like T lymphocyte development

Mihalis Verykokakis | Barbara L Kee

http://ift.tt/2Hh1Sz8

Chemical sensing in development and function of intestinal lymphocytes

Luisa Cervantes-Barragan | Marco Colonna

http://ift.tt/2GgcHjF

Toxicological profile and safety pharmacology of a single dose of fibroblast activation protein-α-based doxorubicin prodrug: in-vitro and in-vivo evaluation

Fibroblast activation protein-α (FAPα) is a promising tumor-associated target expressed by reactive stromal fibroblasts in tumor tissue. FAPα has a postprolyl peptidase activity and can specifically cleave N-terminal benzyloxycarbonyl (Z)-blocked peptides, such as the substrate Z-Gly-Pro-AMC. Doxorubicin (DOX) is an effective antitumor drug, but its application is greatly limited by toxic adverse effects owing to poor tumor selectivity. Based on these facts, we previously designed a FAPα-targeting prodrug of doxorubicin (FTPD) which can be selectively hydrolyzed by FAPα. FTPD can retain potent antitumor efficacy and has favorable tumor targeting. The present study aimed to further evaluate the toxicological profile and the safety pharmacological property of FTPD in vitro and in vivo. The cytotoxicity assay showed that FTPD displayed markedly lower cytotoxicity to 3T3 cells and HEK-293 cells compared with DOX. In the short-term toxicity study, mice treated with 25 mg/kg of FTPD showed no obvious change in the appearance and general behavior, and no case of mortality was observed within 14 days. Unlike DOX, FTPD exhibited reduced toxicity to heart, liver, kidney, spleen as well as peripheral white blood cells in mice. Moreover, open file test and general pharmacology study were also conducted correspondingly in mice and beagle dogs. It was found that FTPD may not produce significant pharmacological effects on spontaneous locomotor activity and cardiovascular-respiratory system except for a transient decreasing in systolic blood pressure. Taken together, the results of this work suggest that FTPD has more favorable toxicological profile and better drug safety compared with its parent drug DOX.

http://ift.tt/2GjV4zz

Antitumor effect of the Newcastle disease viral hemagglutinin–neuraminidase gene is expressed through an oncolytic adenovirus effect in osteosarcoma cells

Newcastle disease virus (NDV) can specifically kill cancer cells and has less toxicity to normal cells. The hemagglutinin–neuraminidase (HN) protein is an important structural protein in NDV pathogenesis and has been postulated as a promising candidate for antitumor therapy. The aim of this study was to investigate the anticancer potential of recombinant adenovirus Ad-HN-PEG3p-E1a. An MTS assay was performed to determine viral proliferation after viral infection, the data showed that the proliferation ability of osteosarcoma cells decreased, whereas there was no significant change in normal hepatic cells. DAPI and Annexin V experiments showed that osteosarcoma cells were killed because of apoptosis, active oxygen content, and augmented mitochondrial membrane potential loss. Caspase Activity Assay Kits were used to detect the caspase-3 activities of the treated OS-732 for increased expression. Western blot analysis showed that cytochrome C increased significantly and apoptosis of the virus was confirmed in tumor cells. In-vivo experiments show that NDV has an inhibitory effect on tumor growth. The recombinant adenovirus, which is composed of a HN protein and progressive increment promoter PEG3p, could inhibit the growth of OS-732 and promote the apoptosis of tumor cells. However, there was no clear relationship with normal cell (L02) apoptosis.

http://ift.tt/2HkEEYT

Sonic hedgehog and Wnt/β-catenin pathways mediate curcumin inhibition of breast cancer stem cells

Cancer stem cells (CSCs) play an essential role in the progression of many tumors. Sonic hedgehog (Shh) and Wnt/β-catenin pathways are crucial in maintaining the stemness of CSCs. Curcumin has been shown to possess anticancer activity. However, the interventional effect of curcumin on breast CSCs has not been elucidated. In the present study, we investigated the role of Shh and Wnt/β-catenin pathway in curcumin inhibition of breast CSCs. We showed that the levels of breast CSCs markers were significantly elevated in SUM159 and MCF7 sphere-forming cells. We further illustrated that curcumin effectively decreased breast CSCs activity by inhibiting tumor sphere formation, decreasing breast CSCs markers (CD44, ALDH1A1, Nanog, and Oct4), as well as inhibiting proliferation and inducing apoptosis. Moreover, we showed that downregulation of Shh and Wnt/β-catenin activity resulted in breast CSCs inhibition; curcumin exerted an inhibitory effect on breast CSCs by suppressing both Shh and Wnt/β-catenin pathways. Taken together, these results indicated curcumin inhibition of breast CSCs by downregulation of Shh and Wnt/β-catenin pathways. Findings from this study could provide new insights into the potential therapeutic application of curcumin in breast CSCs elimination and cancer intervention.

http://ift.tt/2GhOOrU

Palbociclib has no clinically relevant effect on the QTc interval in patients with advanced breast cancer

The aim of this study was to assess the potential effects of palbociclib in combination with letrozole on QTc. PALOMA-2, a phase 3, randomized, double-blind, placebo-controlled trial, compared palbociclib plus letrozole with placebo plus letrozole in postmenopausal women with estrogen receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer. The study included a QTc evaluation substudy carried out as a definitive QT interval prolongation assessment for palbociclib. Time-matched triplicate ECGs were performed at 0, 2, 4, 6, and 8 h at baseline (Day 0) and on Cycle 1 Day 14. Additional ECGs were collected from all patients for safety monitoring. The QT interval was corrected for heart rate using Fridericia's correction (QTcF), Bazett's correction (QTcB), and a study-specific correction factor (QTcS). In total, 666 patients were randomized 2 : 1 to palbociclib plus letrozole or placebo plus letrozole. Of these, 125 patients were enrolled in the QTc evaluation substudy. No patients in the palbociclib plus letrozole arm of the substudy (N=77) had a maximum postbaseline QTcS or QTcF value of ≥ 480 ms, or a maximum increase from clock time-matched baseline for QTcS or QTcF values of ≥ 60 ms. The upper bounds of the one-sided 95% confidence interval for the mean change from time-matched baseline for QTcS, QTcF, and QTcB at all time points and at steady-state Cmax following repeated administration of 125 mg palbociclib were less than 10 ms. Palbociclib, when administered with letrozole at the recommended therapeutic dosing regimen, did not prolong the QT interval to a clinically relevant extent.

http://ift.tt/2HkvPhO

FoxM1 promotes epithelial–mesenchymal transition, invasion, and migration of tongue squamous cell carcinoma cells through a c-Met/AKT-dependent positive feedback loop

Forkhead box protein M1 (FoxM1) has been associated with cancer progression and metastasis. However, the function of FoxM1 in tongue squamous cell carcinoma (TSCC) remains largely unknown. The purpose of this study was to determine the role of FoxM1 in regulation of epithelial–mesenchymal transition (EMT) and migration of TSCC cells. We found that FoxM1 induced EMT and increased invasion/migration capacity in SCC9 and SCC25 cells. FoxM1 stimulation increased c-Met, pAKT, and vimentin levels but decreased E-cadherin level. Chromatin immunoprecipitation assay established that FoxM1 is bound to the promoter of c-Met to activate its transcription. In turn, c-Met promoted the expression of FoxM1 and pAKT. Blocking AKT signaling attenuated the invasion and migration of SCC9 and SCC25 cells stimulated by FoxM1 or c-Met. These results indicate that a positive feedback loop controls the EMT and migration of TSCC cells induced by FoxM1 and c-Met through AKT. Furthermore, the expression levels of FoxM1, pAKT, and c-Met were found to significantly increase in TSCC tissues compared with normal tissues, and these three biomarkers were concomitantly expressed in TSCC tissues. Clinical association analyses indicated that the expression of FoxM1, c-Met, and pAKT was associated with clinicopathological characteristics of patients with TSCC including tumor stage, tumor size, and lymph node metastasis. Taken together, our findings suggest that FoxM1 promotes the EMT, invasion and migration of TSCC cells, and cross-talks with c-Met/AKT signaling to form a positive feedback loop to promote TSCC development.

http://ift.tt/2Gj9sIt

Antileukemic effects of neurokinin-1 receptor inhibition on hematologic malignant cells: a novel therapeutic potential for aprepitant

Genetic and laboratory studies have remodeled the conventional understanding of cancer pathogenesis by identifying different molecular alterations. Intrigued by the contribution of neurokinin-1 receptor (NK1R) network in cancer pathogenesis, we investigated the antileukemic effects of aprepitant, a nonpeptide antagonist of NK1R, in a panel of hematological cell lines. In this study, we found that aprepitant decreased the survival of all the tested cells; however, as compared with NB4, viability of the other cell lines was inhibited at higher concentrations. By increasing both p21 and p73 along with suppressing c-Myc and hTERT, aprepitant probably disordered cell distribution in the cell cycle, decreased DNA replication rate, and, thereby, impeded the proliferative capability of NB4 cells. Moreover, exposing cells to this agent led to activation of the caspase-3-dependent apoptotic pathway through altering the expression of apoptosis-related genes. Noteworthy, aprepitant also sensitized NB4 cells to the cytotoxic effects of arsenic trioxide and vincristine. Overall, it seems that pharmaceutical targeting of NK1R using aprepitant, either as a single agent or in combination, possesses novel promising potential for leukemia treatment strategies.

http://ift.tt/2HkIqSg

Sodium butyrate increases P-gp expression in lung cancer by upregulation of STAT3 and mRNA stabilization of ABCB1

As a new type of anticancer drug, the effect of histone deacetylase inhibitors (HDACIs) in cancer clinical therapy is disappointing owing to drug resistance. P-glycoprotein (P-gp) is clearly recognized as a multidrug resistance protein. However, the relationship between P-gp and sodium butyrate (SB), a kind of HDACIs, has not been investigated. In this study, we found that SB increased mRNA and protein expression of P-gp in lung cancer cells and the underlying mechanisms were elucidated. We found that SB treatment enhanced the mRNA and protein expression of STAT3 rather than that of β-catenin, Foxo3a, PXR, or CAR, which were reported to directly regulate the transcription of ABCB1, a P-gp-encoding gene. Interestingly, inhibition of STAT3 expression obviously attenuated SB-increased P-gp expression in lung cancer cells, indicating that STAT3 played an important role in SB-mediated P-gp upregulation. Furthermore, we found that SB increased the mRNA stability of ABCB1. In summary, this study showed that SB increased P-gp expression by facilitating transcriptional activation and improving ABCB1 mRNA stability. This study indicated that we should pay more attention to HDACIs during cancer clinical therapy.

http://ift.tt/2GheBkc

Antitumor effects of histone deacetylase inhibitor suberoylanilide hydroxamic acid in epidermal growth factor receptor-mutant non-small-cell lung cancer lines in vitro and in vivo

Histone acetylation is one of the most abundant post-translational modifications in eukaryotic cells; aberrant histone acetylation is related to a range of cancer types because of the dysregulation of histone deacetylases (HDACs). Inhibition of HDACs leads to suppression of tumor growth in multiple cancers, whereas the inhibitory effects of HDAC inhibitors remain incompletely understood in epidermal growth factor receptor (EGFR)-mutant lung cancers. In this study, the antitumor effects of HDACs inhibitor suberoylanilide hydroxamic acid (SAHA, vorinostat) were examined in EGFR-mutant lung cancer cell lines. The results of the present work showed that SAHA markedly inhibited cell viability and proliferation, induced cell apoptosis by arresting the cell cycle in the G2/M phase, and significantly reduced tumor growth in a xenograft model. Further study confirmed that the suppression function of SAHA might be mediated by regulating the ERK-dependent and/or the AKT-dependent pathway; meanwhile, angiogenesis abrogation induced by SAHA exerted effects on tumor regression in vivo. Taken together, our results identify the antitumor effects of HDACs inhibitor SAHA as an alternative therapeutic application for the epigenetic treatment of EGFR-mutant non-small-cell lung cancer.

http://ift.tt/2Hh1DEe

Dioscin inhibits colon cancer cells’ growth by reactive oxygen species-mediated mitochondrial dysfunction and p38 and JNK pathways

Dioscin is a natural steroid saponin derived from several plants that shows potent anticancer effects against a variety of cancer cells. Here, we investigated the antitumor effect of dioscin against human colon cancer cells and evaluated the molecular mechanism involved in this process. The cell cytotoxicity was studied by the MTT assay and BrdU incorporation. The proapoptotic mechanism of dioscin was characterized by flow cytometry analysis. A western blot and an immunofluorescence staining were used to investigate how dioscin induces apoptosis in vitro. In our study, dioscin could significantly inhibit the growth of colon cancer cells in a time-dependent and dose-dependent manner. Dioscin induces apoptosis and reactive oxygen species (ROS) generation, promoting the disruption of mitochondrial membrane potential, Bax translocation to the mitochondria, cytochrome C release to cytosol, activations of caspase-9/3, PARP cleavage, and subsequent apoptosis. Dioscin-induced apoptosis was accompanied by sustained phosphorylation of JNK, p38-MAPK. N-acetyl-L-cysteine, a scavenger of ROS, significantly reversed dioscin-induced cell death and activation of JNK and p38. Collectively, the data indicate that the induction of apoptosis by dioscin is mediated through ROS proteins, which are critical upstream signals for JNK/p38-MAPK activation.

http://ift.tt/2GfSsCM

Erlotinib for coexisting typical bronchial carcinoid and advanced lung adenocarcinoma: does the epidermal growth factor receptor mutation status matter?

Adenocarcinoma (AC) is the most common type of primary pulmonary malignancy. Lung carcinoid, however, is a rare neuroendocrine tumor. Their coexistence is extremely uncommon. We report the unique case of synchronous advanced lung AC of the right upper lobe (stage IIIB) and typical endobronchial carcinoid tumor in the contralateral lower lobe in a 49-year-old white female who had never smoked. PET-computed tomography scan revealed a fluorine-18-fluorodeoxyglucose-avid AC lesion, whereas the carcinoid tumor was fluorine-18-fluorodeoxyglucose occult. After two lines of platinum-based combination chemotherapies and radiotherapy, the AC progressed, and oral tyrosine kinase inhibitor therapy with erlotinib was initiated in third line. On erlotinib, the AC remained stable for 50 months until disease progression, whereas the carcinoid completely regressed. Molecular testing of the rebronchoscopied AC revealed an exon 19 deletion mutation in the epidermal growth factor receptor (EGFR) gene, whereas the carcinoid was retrospectively EGFR mutation negative. The patient eventually succumbed to ileus caused by intra-abdominal spread of disease, surviving a remarkable 80 months with good performance status throughout most of the follow-up period. To the best of our knowledge, this is the first reported case of synchronous primary lung cancers with different EGFR mutation status, describing an unexpected response of an EGFR-wild-type carcinoid to third-line erlotinib.

http://ift.tt/2Hixbd1

Reply to ‘Comment on ‘Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis”

http://ift.tt/2sEOOkb

The predictive and prognostic potential of plasma telomerase reverse transcriptase (TERT) RNA in rectal cancer patients

http://ift.tt/2EHsmeO

Comment on ‘Prognostic biomarkers for oral tongue squamous cell carcinoma: a systematic review and meta-analysis’

http://ift.tt/2Bwy01k

Sensing Danger after Kidney Transplantation

No abstract available

http://ift.tt/2F7QIfI

3D Endoscopic Donor Nephrectomy Versus Robot-Assisted Donor Nephrectomy: a Detailed Comparison of 2 Prospective Cohorts

AbstractBackgroundThere are 2 endoscopic surgical techniques that implement 3D vision to overcome visual misperception: 3D endoscopy and the da Vinci surgical system. 3D endoscopy has several advantages, such as the presence of tactile feedback and easy implementation, at lower costs. We aimed to assess whether 3D endoscopy could be an alternative to the robot during living donor nephrectomy (LDN).MethodsBetween April 2015 and April 2016 we prospectively collected data on 40 patients undergoing 3D endoscopic LDNs in 1 center, performed by a da Vinci certified surgeon. Data on donors' perioperative results and recipient and graft survival were collected. These data were compared to 40 robot-assisted donor nephrectomies (RADNs) performed in the same center (between January 2012 and May 2014).ResultsBaseline characteristics for both groups were comparable. Intraoperative results showed a significantly shorter median skin-to-skin time (STS-time) of 138.5 min. (125.8-163.8) versus 169.0 (141.5-209.8) min. in favour of the 3D group (P=0.001). Warm ischemia time ([WI-time], P=0.003) and hilar phase for both single- (1 artery and vein) and multiple anatomies (≥1 artery and/or vein [P=0.002 and P=0.010, respectively]) were also significantly reduced in favour of the 3D group, with a flat learning curve. Follow-up demonstrated no readmissions, nor significant differences for donors, recipients and graft survival.Conclusions3D endoscopy may be a good alternative to RADN, since morbidity, graft and recipient survival were comparable, with a significantly shorter median STS-time, WI-time and hilar dissection phase. Furthermore, implementation was easy and at lower costs, whilst tactile feedback was preserved. Background There are 2 endoscopic surgical techniques that implement 3D vision to overcome visual misperception: 3D endoscopy and the da Vinci surgical system. 3D endoscopy has several advantages, such as the presence of tactile feedback and easy implementation, at lower costs. We aimed to assess whether 3D endoscopy could be an alternative to the robot during living donor nephrectomy (LDN). Methods Between April 2015 and April 2016 we prospectively collected data on 40 patients undergoing 3D endoscopic LDNs in 1 center, performed by a da Vinci certified surgeon. Data on donors' perioperative results and recipient and graft survival were collected. These data were compared to 40 robot-assisted donor nephrectomies (RADNs) performed in the same center (between January 2012 and May 2014). Results Baseline characteristics for both groups were comparable. Intraoperative results showed a significantly shorter median skin-to-skin time (STS-time) of 138.5 min. (125.8-163.8) versus 169.0 (141.5-209.8) min. in favour of the 3D group (P=0.001). Warm ischemia time ([WI-time], P=0.003) and hilar phase for both single- (1 artery and vein) and multiple anatomies (≥1 artery and/or vein [P=0.002 and P=0.010, respectively]) were also significantly reduced in favour of the 3D group, with a flat learning curve. Follow-up demonstrated no readmissions, nor significant differences for donors, recipients and graft survival. Conclusions 3D endoscopy may be a good alternative to RADN, since morbidity, graft and recipient survival were comparable, with a significantly shorter median STS-time, WI-time and hilar dissection phase. Furthermore, implementation was easy and at lower costs, whilst tactile feedback was preserved. Corresponding author: T.C.K. Tran, MD, Erasmus MC, Department of Surgery's-Gravendijkwal 230, 3015 CE Rotterdam, The Netherlands. Email: t.tran@erasmusmc.nl. Tel. number: 00317031810. Fax number: 00317032396 Authorship Page Participated in research design: Mulder, Janki, Terkivatan, Klop, IJzermans, Tran Participated in the writing of the paper: Mulder, Janki, Tran Participated in the performance of the research: Mulder, Janki, Terkivatan, Klop, IJzermans, Tran Participated in data analysis: Mulder, Janki, Klop, IJzermans, Tran Critical revision: Mulder, Janki, Terkivatan, Klop, IJzermans, Tran Disclosure The study was supported by Olympus Netherlands B.V., who provided all necessary equipment for free, and the Erasmus MC Efficiency Research grant. E.E.A.P. Mulder, S. Janki, T. Terkivatan, K.W.J. Klop, J.N.M. IJzermans and T.C.K. Tran declare no conflicts of interest or financial ties; neither the investigators nor subjects received compensation for the performance of the study, and the investigators had control of the presentation of the data. Copyright © 2018 Wolters Kluwer Health, Inc. All rights reserved.

http://ift.tt/2EvzLdM

Ganja, No Barrier for Liver Transplantation?

No abstract available

http://ift.tt/2F2U3fL

Dose Sculpting Intensity Modulated Radiation Therapy for Vertebral Body Sparing in Children with Neuroblastoma

Long-term survivors of high-risk neuroblastoma have an increased incidence of musculoskeletal anomalies. Historically, the radiation field to the primary site was designed to cover adjacent vertebral bodies to minimize growth deformities. With intensity modulated radiotherapy (IMRT), one can shape dose distributions to spare vertebral bodies without sacrificing tumor coverage. We reviewed our institution's experience with dose sculpting IMRT to assess its effect on vertebral body growth.

http://ift.tt/2GdHFJa

The knowledge, attitudes and practices of doctors regarding antibiotic resistance at a tertiary care institution in the Caribbean

Antibiotic resistance (ABR) is a serious threat that requires coordinated global intervention to prevent its spread. There is limited data from the English-speaking Caribbean.

http://ift.tt/2o73kva

Paving the way for disorders of consciousness diagnosis and prognosis: the role of cardiac autonomic response and beyond

Following coma due to severe brain injury, a patient can wake up or progress into an Unresponsive wakefulness syndrome (UWS) or Minimally Conscious State (MCS). These entities are characterized by preserved wakefulness and completely (UWS) or partially (MCS) impaired awareness. The functional and behavioral outcome of these patients is rather difficult to predict, as many factors come into play, including the type and severity of brain injury and, in particular, the level of awareness, which is assessed by using specific clinical scales that quantify the behavioral responsiveness (e.g., the Coma Recovery Scale-Revised).

http://ift.tt/2HjWcEK

The phenotypic heterogeneity of hereditary diffuse gastric cancer: the report of one family with early-onset disease

The time-course for the development of clinically significant hereditary diffuse gastric cancer (HDGC) is unpredictable. Little is known about the progression from pre-clinical, indolent lesions to widely invasive, aggressive phenotypes. Gastro-endoscopy often fails to detect early lesions and risk-reducing/prophylactic total gastrectomy (PTG) is the only curative approach.We present a HDGC family with early-onset disease, in which clinical and histological findings provided insight into the understanding of different HDGC phenotypes.

http://ift.tt/2sz6ehS

Among Patients With Intracerebral Hemorrhage, Is Intensive Blood Pressure Decreasing Associated With Improved Outcome?

Five trials (N=4,360) met inclusion criteria out of 1,495 identified citations. The definition for intensive blood pressure control varied among the studies and included a systolic blood pressure range of 110 to 150 mm Hg. Standard blood pressure was defined as a systolic pressure of 180 mm Hg in 3 studies and 140 to 179 mm Hg in 1 study, and a mean arterial pressure of 110 to 130 mm Hg in 1 study. The risk of bias was low. No measurements of functional status differed between intensive and standard blood pressure control (Table).

http://ift.tt/2Cnjbek

A survey of workplace violence against physicians in the hospitals, Myanmar

Workplace violence in hospitals is recently becoming a major global concern in many countries. However, in Myanmar, we have felt that patients and their families have rarely made unreasonable complaints in hos...

http://ift.tt/2ELsiL0

Meeting Report: The 8th Barossa Meeting—Cell Signaling in Cancer Medicine in the Barossa Valley, Australia

Meeting Report: The 8th Barossa Meeting—Cell Signaling in Cancer Medicine in the Barossa Valley, Australia

Meeting Report: The 8th Barossa Meeting—Cell Signaling in Cancer Medicine in the Barossa Valley, Australia, Published online: 15 February 2018; doi:10.1038/s41419-018-0285-7

Meeting Report: The 8th Barossa Meeting—Cell Signaling in Cancer Medicine in the Barossa Valley, Australia

http://ift.tt/2o9pOMh

CAR-T cells: the long and winding road to solid tumors

CAR-T cells: the long and winding road to solid tumors

CAR-T cells: the long and winding road to solid tumors, Published online: 15 February 2018; doi:10.1038/s41419-018-0278-6

CAR-T cells: the long and winding road to solid tumors

http://ift.tt/2EJt1MF

Gambogenic acid inhibits fibroblast growth factor receptor signaling pathway in erlotinib-resistant non-small-cell lung cancer and suppresses patient-derived xenograft growth

Gambogenic acid inhibits fibroblast growth factor receptor signaling pathway in erlotinib-resistant non-small-cell lung cancer and suppresses patient-derived xenograft growth

Gambogenic acid inhibits fibroblast growth factor receptor signaling pathway in erlotinib-resistant non-small-cell lung cancer and suppresses patient-derived xenograft growth, Published online: 15 February 2018; doi:10.1038/s41419-018-0314-6

Gambogenic acid inhibits fibroblast growth factor receptor signaling pathway in erlotinib-resistant non-small-cell lung cancer and suppresses patient-derived xenograft growth

http://ift.tt/2o8JKyU

ALS-related human cortical and motor neurons survival is differentially affected by Sema3A

ALS-related human cortical and motor neurons survival is differentially affected by Sema3A

ALS-related human cortical and motor neurons survival is differentially affected by Sema3A, Published online: 15 February 2018; doi:10.1038/s41419-018-0294-6

ALS-related human cortical and motor neurons survival is differentially affected by Sema3A

http://ift.tt/2o1PStg

NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer

NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer

NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer, Published online: 15 February 2018; doi:10.1038/s41419-018-0333-3

NIT1 suppresses tumour proliferation by activating the TGFβ1–Smad2/3 signalling pathway in colorectal cancer

http://ift.tt/2o8Jjog

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD+/SIRT1/SUV39H1/H3K9me3 signaling pathway

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD⁺/SIRT1/SUV39H1/H3K9me3 signaling pathway

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD⁺/SIRT1/SUV39H1/H3K9me3 signaling pathway, Published online: 15 February 2018; doi:10.1038/s41419-018-0297-3

Norisoboldine, a natural AhR agonist, promotes Treg differentiation and attenuates colitis via targeting glycolysis and subsequent NAD⁺/SIRT1/SUV39H1/H3K9me3 signaling pathway

http://ift.tt/2o3JDVY

CRISPR whole-genome screening identifies new necroptosis regulators and RIPK1 alternative splicing

CRISPR whole-genome screening identifies new necroptosis regulators and RIPK1 alternative splicing

CRISPR whole-genome screening identifies new necroptosis regulators and <i>RIPK1</i> alternative splicing, Published online: 15 February 2018; doi:10.1038/s41419-018-0301-y

CRISPR whole-genome screening identifies new necroptosis regulators and RIPK1 alternative splicing

http://ift.tt/2oba3nV

Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN

Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN

Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN, Published online: 15 February 2018; doi:10.1038/s41419-018-0305-7

Long noncoding RNA MEG3 suppresses liver cancer cells growth through inhibiting β-catenin by activating PKM2 and inactivating PTEN

http://ift.tt/2EGP7zI

Endometriosis: clinical features, MR imaging findings and pathologic correlation

Abstract

Objective

We illustrate the magnetic resonance imaging (MRI) features of endometriosis.

Background

Endometriosis is a chronic gynaecological condition affecting women of reproductive age and may cause pelvic pain and infertility. It is characterized by the growth of functional ectopic endometrial glands and stroma outside the uterus and includes three different manifestations: ovarian endometriomas, peritoneal implants, deep pelvic endometriosis. The primary locations are in the pelvis; extrapelvic endometriosis may rarely occur. Diagnosis requires a combination of clinical history, invasive and non-invasive techniques. The definitive diagnosis is based on laparoscopy with histological confirmation. Diagnostic imaging is necessary for treatment planning. MRI is as a second-line technique after ultrasound. The MRI appearance of endometriotic lesions is variable and depends on the quantity and age of haemorrhage, the amount of endometrial cells, stroma, smooth muscle proliferation and fibrosis. The purpose of surgery is to achieve complete resection of all endometriotic lesions in the same operation.

Conclusion

Owing to the possibility to perform a complete assessment of all pelvic compartments at one time, MRI represents the best imaging technique for preoperative staging of endometriosis, in order to choose the more appropriate surgical approach and to plan a multidisciplinary team work.

Teaching Points

• Endometriosis includes ovarian endometriomas, peritoneal implants and deep pelvic endometriosis.

• MRI is a second-line imaging technique after US.

• Deep pelvic endometriosis is associated with chronic pelvic pain and infertility.

• Endometriosis is characterized by considerable diagnostic delay.

• MRI is the best imaging technique for preoperative staging of endometriosis.

http://ift.tt/2o2SoQ7

ECR 2018 - BOOK OF ABSTRACTS

http://ift.tt/2o9W7KV

Major pancreatic resections: normal postoperative findings and complications

Abstract

Objectives

(1) To illustrate and describe the main types of pancreatic surgery; (2) to discuss the normal findings after pancreatic surgery; (3) to review the main complications and their radiological findings.

Background

Despite the decreased postoperative mortality, morbidity still remains high resulting in longer hospitalisations and greater costs. Imaging findings following major pancreatic resections can be broadly divided into "normal postoperative alterations" and real complications. The former should regress within a few months whereas complications may be life-threatening and should be promptly identified and treated.

Imaging findings

CT is the most effective postoperative imaging technique. MRI and fluoroscopy are used less often and only in specific cases such as assessing the gastro-intestinal function or the biliary tree. The most common normal postoperative findings are pneumobilia, perivascular cuffing, fluid collections, lymphadenopathy, acute anastomotic oedema and stranding of the peri-pancreatic/mesenteric fat. Imaging depicts the anastomoses and the new postoperative anatomy. It can also demonstrate early and late complications: pancreatic fistula, haemorrhage, delayed gastric emptying, hepatic infarction, acute pancreatitis of the remnant, porto-mesenteric thrombosis, abscess, biliary anastomotic leaks, anastomotic stenosis and local recurrence.

Conclusions

Radiologists should be aware of surgical procedures, postoperative anatomy and normal postoperative imaging findings to better detect complications and recurrent disease.

Teaching Points

• Morbidity after pancreatic resections is high.

• CT is the most effective postoperative imaging technique.

• Imaging depicts the anastomoses and the new postoperative anatomy.

• Pancreatic fistula is the most common complication after partial pancreatic resection.

http://ift.tt/2o3oSdf

Imaging of the scrotum: beyond sonography

Abstract

The aim of this article is to describe the role of second-level imaging techniques after an initial ultrasonography evaluation in the assessment of scrotal diseases. While ultrasonography remains central as the primary imaging modality for the evaluation of pathologic conditions of the scrotum, the role of magnetic resonance imaging continues to evolve: it can actually be valuable as a problem-solving tool when sonographic findings are equivocal or inconclusive. Magnetic resonance imaging of the scrotum may provide accurate detection and characterization of scrotal diseases, well depicting the precise location of scrotal masses (intratesticular or extratesticular) and reliably characterizing benign conditions simulating neoplastic processes, thus preventing unnecessary radical surgery. Advanced magnetic resonance techniques, most of all diffusion weighted imaging and magnetic resonance spectroscopy, play in the meanwhile a more significant role in evaluating scrotal diseases.

Teaching points

• Multiparametric ultrasonography usually represents the initial imaging modality for approaching scrotal diseases.

• MRI is well established as a problem-solving tool for inconclusive sonographic findings.

• Advanced MRI techniques can be successfully applied in scrotal pathology assessment.

• MRI is valuable in differentiating benign conditions from neoplastic processes.

• CT plays a role in trauma assessment and cancer staging alongside PET/CT.

http://ift.tt/2o9W0yZ

Personalized Medicine and Pay for Performance: Should Pharmaceutical Firms be Fully Penalized when Treatment Fails?

Abstract

In this article, we model the behavior of a pharmaceutical firm that has marketing authorization for a new therapy believed to be a candidate for personalized use in a subset of patients, but that lacks information as to why a response is seen only in some patients. We characterize the optimal outcome-based reimbursement policy a health authority should follow to encourage the pharmaceutical firm to undertake research and development activities to generate the information needed to effectively stratify patients. Consistent with the literature, we find that for a pharmaceutical firm that does not undertake research and development activities, when the treatment fails, the total price of the drug must be returned to the healthcare system (full penalization). By contrast, if the firm undertakes research and development activities that make the implementation of personalized medicine possible, treatment failure should not be fully penalized. Surprisingly, in some cases, particularly for high-efficacy drugs and small target populations, the optimal policy may not require any penalty for treatment failure. To illustrate the main results of the analysis, we provide a numerical simulation and a graphical analysis.

http://ift.tt/2EwV96H

Chronic lymphocytic leukemia cells acquire regulatory B-cell properties in response to TLR9 and CD40 activation

Abstract

Circulating chronic lymphocytic leukemia (CLL) cells share phenotypic features with certain subsets of regulatory B-cells (Bregs). The latter cells have been reported to negatively regulate immune cell responses, mostly by provision of IL-10. The purpose of the current study was to identify and delineate Breg properties of CLL cells. B-cells and T-cells were obtained from the peripheral blood of untreated CLL patients diagnosed according to the 2008 Guidelines of the International Workshop on Chronic Lymphocytic Leukemia. Co-culture assays were used to examine the ability of CLL cells to suppress autologous T-cell immune responses. IL-10 potency of CLL cells was assessed following stimulation with activators of the toll-like receptor 9 (TLR9) or CD40 and was correlated with the inhibitory activity of the cells. TLR9-activated CLL cells were found to increase the frequency of CD4⁺CD25^hiFOXp3⁺ regulatory T-cells (Tregs) and to inhibit autologous CD4⁺ T-cell proliferation. This signaling cascade proved to control IL-10 generation in CLL cells, which in turn promoted the inhibition of T-cell proliferation by CLL cells. However, CD40 activation of CLL cells, while exhibiting a similar ability to augment Treg frequency, did not either affect IL-10 generation or T-cell proliferation. In conclusion, CLL cells demonstrate a unique clonal quality of adopting Breg properties which promote modulation of T-cell characteristics. TLR9 appears to be a potent activator of regulatory abilities in CLL cells, possibly contributing to preferential immune escape of TLR9-responsive cells.

http://ift.tt/2C2PB29

Occupational exposure to HIV in a developing country: assessing knowledge and attitude of healthcare professional before and after an awareness symposium

Health care providers (HCPs) are at risk of occupational exposure to HIV infection. In developing world these exposure occur due to general lack of awareness, education and structured training of HCPs. The obj...

http://ift.tt/2Hkap4D

T-ARMS PCR genotyping of SNP rs445709131 using thermostable strand displacement polymerase

In a recent publication, we reported the successful use of tetra primer-amplification refractory mutation system based polymerase chain reaction (T-ARMS-PCR) for genotyping of rs445709131-SNP responsible for t...

http://ift.tt/2GfRnLo

Prevalence of erectile dysfunction and associated factors among diabetic men attending the diabetic clinic at Felege Hiwot Referral Hospital, Bahir Dar, North West Ethiopia, 2016

Even though several scholars have conducted study in different part of the world on erectile dysfunction in patients diagnosed with diabetes mellitus, it's magnitude vary among their finding with the range bet...

http://ift.tt/2Hi61D3

High-density lipoprotein (HDL) promotes angiogenesis via S1P3-dependent VEGFR2 activation

Abstract

High-density lipoprotein (HDL) has previously been shown to promote angiogenesis. However, the mechanisms by which HDL enhances the formation of blood vessels remain to be defined. To address this, the effects of HDL on the proliferation, transwell migration and tube formation of human umbilical vein endothelial cells were investigated. By examining the abundance and phosphorylation (i.e., activation) of the vascular endothelial growth factor receptor VEGFR2 and modulating the activity of the sphingosine-1 phosphate receptors S1P1–3 and VEGFR2, we characterized mechanisms controlling angiogenic responses in response to HDL exposure. Here, we report that HDL dose-dependently increased endothelial proliferation, migration and tube formation. These events were in association with increased VEGFR2 abundance and rapid VEGFR2 phosphorylation at Tyr1054/Tyr1059 and Tyr1175 residues in response to HDL. Blockade of VEGFR2 activation by the VEGFR2 inhibitor SU1498 markedly abrogated the pro-angiogenic capacity of HDL. Moreover, the S1P3 inhibitor suramin prevented VEGFR2 expression and abolished endothelial migration and tube formation, while the S1P1 agonist CYM-5442 and the S1P2 inhibitor JTE-013 had no effect. Last, the role of S1P3 was further confirmed in regulation of S1P-induced endothelial proliferation, migration and tube formation via up-regulation and activation of VEGFR2. Together, these findings argue that HDL promotes angiogenesis via S1P3-dependent up-regulation and activation of VEGFR2 and also suggest that the S1P–S1P3–VEGFR2 signaling cascades as a novel target for HDL-modulating therapy implicated in vascular remodeling and functional recovery in atherosclerotic diseases such as myocardial infarction and ischemic stroke.

http://ift.tt/2o6Xv0M

Design Factors of Femur Fracture Fixation Plates made of Shape Memory Alloy based on the Taguchi Method by Finite Element Analysis

Abstract

This study proposed a way to design femur fracture fixation plates made of shape memory alloy based on CT (Computed Tomography) images of Korean cadaveric femurs. To this end, 3 major design factors of femur fracture fixation plates (circumference angle, thickness, and inner diameter) were selected based on the contact pressure when a femur fracture fixation plate was applied to a cylinder model using the Taguchi Method. Then the effects of the design factors were analyzed.

It was shown that the design factors were statistically significant at a level of p=0.05 concerning the inner diameter and the thickness. The factors affecting the contact pressure were inner diameter, thickness, and circumference angle, in that order. Particularly, in the condition of Case 9 (inner diameter 27 mm, thickness 2.4 mm, and circumference angle 270 deg), the max. average contact pressure was 21.721 MPa, while the min. average contact pressure was 3.118 MPa in Case 10 (inner diameter 29 mm, thickness 2.0 mm, and circumference angle 210 deg).

When the femur fracture fixation plate was applied to the cylinder model, the displacement due to external sliding and pulling forces was analyzed. As a result, the displacement in the sliding condition was at max. 3.75 times greater than that in the pulling condition, which indicated that the cohesion strength between the femur fracture fixation plate and the cylinder model was likely to be greater in the pulling condition.

When a human femur model was applied, the max. average contact pressure was 10.76 MPa, which was lower than the yield strength of a human femur (108 MPa). In addition, the analysis of the rib behaviors of the femur fracture fixation plate in relation to the recovery effect of the shape memory alloy, showed that the rib behaviors varied depending on the arbitrarily curved shapes of the femur sections.

http://ift.tt/2BvMmix

Abiraterone Approved for Earlier Use in Men with Metastatic Prostate Cancer

The Food and Drug Administration (FDA) has expanded the approval of abiraterone (Zytiga®) for men with prostate cancer. The agency approved abiraterone, in combination with the steroid prednisone, for men with metastatic prostate cancer that is responsive to hormone-blocking treatments (also known as castration-sensitive) and is at high risk of progressing.

http://ift.tt/2Es22BT

RNA versus protein toxicity in C9orf72 ALS/FTLD

http://ift.tt/2EuuOlL

Evidence of amyloid-β cerebral amyloid angiopathy transmission through neurosurgery

Abstract

Amyloid-β (Aβ) is a peptide deposited in the brain parenchyma in Alzheimer's disease and in cerebral blood vessels, causing cerebral amyloid angiopathy (CAA). Aβ pathology is transmissible experimentally in animals and through medical procedures in humans, such as contaminated growth hormone or dura mater transplantation in the context of iatrogenic prion disease. Here, we present four patients who underwent neurosurgical procedures during childhood or teenage years and presented with intracerebral haemorrhage approximately three decades later, caused by severe CAA. None of these patients carried pathogenic mutations associated with early Aβ pathology development. In addition, we identified in the literature four patients with a history of neurosurgical intervention and subsequent development of CAA. These findings raise the possibility that Aβ pathology may be transmissible, as prion disease is, through neurosurgical procedures.

http://ift.tt/2F3oFOh

Early motor signs of autism spectrum disorder in spontaneous position and movement of the head

Abstract

We examined the characteristics of spontaneous movements at 9–20 weeks postterm age in very low birth-weight infants who later developed autism spectrum disorder (ASD). We analyzed video recordings of spontaneous movements of 39 children who had no clinical issues [typically developing (TD) group], 21 children who showed developmental delay, and 14 children who were diagnosed with ASD (ASD group) at 6 years of age. Head position in each video frame was classified by visual inspection. The percentage of midline head position (PMHP) and number of changes in head position were calculated. Spontaneous limb movements were quantified using six indices. The values of PMHP were significantly lower in the ASD group than in the TD group. The lower PMHP during early infancy is associated with later development of ASD. Poorer performance in maintaining midline position of the head at this period may distinguish infants who later develop ASD from those who show TD.

http://ift.tt/2Hh4dds

Breast Milk Enhances Growth of Enteroids: An Ex Vivo Model of Cell Proliferation

This protocol describes how to establish an enteroid culture system from neonatal mouse or premature human intestine as well as an efficient method to collect milk from mice.

http://ift.tt/2F2gfGR

Titration ELISA as a Method to Determine the Dissociation Constant of Receptor Ligand Interaction

A detailed protocol to perform a titration ELISA is described. Moreover, a novel algorithm is presented to evaluate titration ELISAs and to obtain a dissociation constant of binding of a soluble ligand to a microtiter plate-immobilized receptor.

http://ift.tt/2ErRv9P

Severe Adverse Reaction to Vemurafenib in a Pregnant Woman with Metastatic Melanoma

Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction.
Case Rep Oncol 2018;11:119–124

http://ift.tt/2o2cYA2

Lipid-lowering drugs, dyslipidemia, and breast cancer risk in a Medicare population

Abstract

Purpose

We sought to disentangle the effects of statins and other lipid-lowering drugs and the underlying dyslipidemia for which they are prescribed on breast cancer risk.

Methods

We conducted a case–control study within the linked Surveillance, Epidemiology, and End results (SEER)-Medicare data. Cases were women with invasive breast cancer aged 66 + years (N = 30,004) identified by SEER registries (years 2007–2011). Controls were women (N = 198,969) identified from a 5% random sample of Medicare recipients alive and breast cancer free in year of selection. Participants had a minimum of 13 months of Part A, Part B non-health maintenance organization Medicare and Part D Medicare coverage at least 13 months preceding cancer diagnosis/selection. Exposures were assessed until 12 months before diagnosis/control selection. Odds ratios (OR) and 99.9% confidence intervals (CI) were estimated using adjusted unconditional and multinomial logistic regression.

Results

ORs of invasive breast cancer associated with dyslipidemia, statins, and non-statin lipid-lowering drugs were 0.86 (99.9% CI 0.81–0.90), 1.07 (99.9% CI 1.03–1.13) and 1.03 (99.9% CI 0.95–1.11), respectively. Risk reductions with dyslipidemia were slightly greater when untreated than treated and did not vary much by time between dyslipidemia and breast cancer diagnosis. Whether treated or untreated, dyslipidemia was associated with greater reductions in risk for later stage than earlier stage breast cancer (p-heterogeneity < 0.0001).

Conclusions

Lipid-lowering drugs did not account for the lower breast cancer risk associated with dyslipidemia. Our data do not support using statins or other lipid-lowering drugs to prevent breast cancer.

http://ift.tt/2Cl4Crz

Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo

Wu and colleagues show that cancer immunity against multiple types of cancer can be achieved using an easily generalizable iPSC-based cancer vaccine. This immunity is based on overlapping epitopes between iPSCs and cancer cells and can also be achieved by reactivating the immune system as an adjuvant immunotherapy.

http://ift.tt/2Co7aVU

CD150high Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine

Hirata et al. identify a regulatory T cell (Treg) population that localizes in the hematopoietic stem cell (HSC) niche with high-level expression of CD150, an HSC marker. These niche-associated Tregs maintain HSC quiescence and immune privilege through adenosine. Furthermore, transfer of niche Tregs significantly improves allogeneic HSC engraftment.

http://ift.tt/2ExYjXF

Mucin Production and Hydration Responses to Mucopurulent Materials in Normal versus Cystic Fibrosis Airway Epithelia

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 481-491, February 15, 2018.


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Reply to Suissa and Ariel: The FULFIL Trial

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 542-543, February 15, 2018.


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Continuous Negative Abdominal Pressure Recruits Lungs at Lower Distending Pressures

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 534-537, February 15, 2018.


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Mild Elevation of Pulmonary Arterial Pressure as a Predictor of Mortality

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 509-516, February 15, 2018.


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Pulmonary Rehabilitation, an Update: Clinical Phenotypes and Effect of Comorbidities and Echocardiographic Abnormalities

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 517-519, February 15, 2018.


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Comparison of the 2017 and 2015 Global Initiative for Chronic Obstructive Lung Disease Reports. Impact on Grouping and Outcomes

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 463-469, February 15, 2018.


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Sepsis-3 in Community-acquired Pneumonia: How Reliable Is It?

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 537-537, February 15, 2018.


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Peripheral and Alveolar Cell Transcriptional Programs Are Distinct in Acute Respiratory Distress Syndrome

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 528-532, February 15, 2018.


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Low Lung Function in Young Adult Life Is Associated with Early Mortality

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 538-539, February 15, 2018.


http://ift.tt/2EIJAbz

Mucopurulent Triggering of the Airway Epithelium. Implications in Health and Cystic Fibrosis

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 418-420, February 15, 2018.


http://ift.tt/2EFpJKF

Sequestering Damage-associated Molecular Patterns in Critical Illness. A Novel Homeostatic Role for the Erythrocyte

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 416-418, February 15, 2018.


http://ift.tt/2swXl8z

Chronic Thromboembolic Pulmonary Hypertension

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page P5-P6, February 15, 2018.


http://ift.tt/2C30ukg

Under Pressure to Clarify Pulmonary Hypertension Clinical Risk

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 423-426, February 15, 2018.


http://ift.tt/2swrrsF

Novel Blood-based Transcriptional Biomarker Panels Predict the Late-Phase Asthmatic Response

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 450-462, February 15, 2018.


http://ift.tt/2C1zt0P

E-Cigarettes: Mucus Measurements Make Marks

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 420-422, February 15, 2018.


http://ift.tt/2sw10Uh

Systematic Error in Respiratory Impedance Using Commercial Equipment Calibrated according to the Manufacturer’s Instructions

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 532-534, February 15, 2018.


http://ift.tt/2C269r2

Recurrent Respiratory Papillomatosis and Bevacizumab Treatment

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 539-541, February 15, 2018.


http://ift.tt/2sBwQyU

E-Cigarette Use Causes a Unique Innate Immune Response in the Lung, Involving Increased Neutrophilic Activation and Altered Mucin Secretion

American Journal of Respiratory and Critical Care Medicine, Volume 197, Issue 4, Page 492-501, February 15, 2018.


http://ift.tt/2ELclof

Non-Commercial versus Commercial Clinical Trials: a Retrospective Study of the Applications Submitted to a Research Ethics Committee

Summary

There are a lot of difficulties in undertaking independent clinical research without support from the pharmaceutical industry. In this retrospective observational study some design characteristics, the clinical trial public register and the publication rate of non-commercial clinical trials were compared to those of commercial clinical trials.

A total of 809 applications of drug-evaluation clinical trials were submitted from May 2004 to May 2009 to the research ethics committee of a tertiary hospital, and 16.3% of trials were non-commercial. They were mainly phase IV, multicenter national, and unmasked controlled trials, compared to the commercial trials that were mainly phase II- III, multicenter international, and double-blind masked trials. The commercial trials were registered and published more often than non-commercial ones. More funding for non-commercial research is still needed. The results of the research, commercial or non-commercial, have to be disseminated in order not to compromise either its scientific or its social value.

http://ift.tt/2C1sBR5

Incidence of acute suppurative sialadenitis in end-stage cancer patients: a retrospective observational study

Acute suppurative sialadenitis (hereafter referred to as sialadenitis) is accompanied by pain and fever and can diminish the quality of life (QOL) in end-stage cancer patients; however, its incidence is not clear.

http://ift.tt/2o1KgQ3

When do You Start and When do You Stop Screening for Colon Cancer in Inflammatory Bowel Disease?

http://ift.tt/2Bth0cp

What is the Role of the Inflammatory Bowel Disease Panel in Diagnosis and Treatment?

http://ift.tt/2o482dW

Fungal liver abscess in an immunocompetent patient who underwent repeated ERCPs and subtotal cholecystectomy

We report a case of a previously healthy female patient who initially presented with fever, jaundice and right upper quadrant pain three days after dilatation and stenting of a stricture of the common bile duct (CBD). During an earlier admission, the patient had undergone endoscopic retrograde cholangiopancreatography (ERCP) having presented with fevers and biliary dilatation on ultrasound. The ERCP features were more consistent with Mirizzi's Syndrome. The patient subsequently underwent subtotal cholecystectomy and later developed a CBD stricture, requiring repeat ERCP and stent insertion. At presentation, she had moderately deranged liver function tests and significantly elevated inflammatory markers and was found on cross-sectional imaging to have developed a liver abscess. Aspiration of the lesion cultured Candida albicans. She was treated with intravenous antifungals, broad-spectrum antibiotics and further aspiration of abscess, which contributed towards her successful recovery. Fungal liver abscess should be suspected in immunocompetent patients who undergo ERCP and or cholecystectomy.

http://ift.tt/2F44Lmg

Radiographic markers for measuring tibial rotation based on CT-reconstructed radiographs: an accuracy and feasibility study

Abstract

Objectives

Malreduction in the axial plane (malrotation) following tibial fracture surgery is often undiagnosed. A few clinical and radiographic methods have been proposed for measuring tibial rotation intraoperatively, yet have failed to match the accuracy of computed tomography (CT). The aim of this study was to develop radiographic tools for future intraoperative assessment of the tibial shaft rotation profile.

Methods

The setting was a laboratory computerized analysis. Twenty lower limb CT scans were used to construct a three-dimensional (3D) model using AMIRA© software. A virtual 3D cylinder was implanted in the posterior condylar line and in the transmalleolar axis. The 3D models were used to simulate four standard knee and ankle plain radiographs. On each radiograph, four landmarks were depicted by two observers and their relation with the cylinder was measured and analyzed for accuracy and reproducibility. A cadaveric lower leg was implanted with two Kirschner wires. A CT scan was performed in addition to 2D fluoroscopy. The simulated radiographs and the fluoroscopy were compared for accuracy.

Results

Measurement of the landmarks showed reliability in most of the knee anteroposterior and ankle mortise radiographs (coefficients of variation < 0.01 and = 0.01) respectively. Cadaveric measurement of the landmarks using real fluoroscopy and simulated radiographs were similar.

Conclusions

To date, no reliable and common methods have been reported for the evaluation of tibial axial rotation. We propose a model in which simple radiographic landmarks can be used to calculate a 3D coordinate system that accurately assesses the axial rotation angle of the tibial shaft.

http://ift.tt/2Gg5fFm

Middle-aged female with palpable swelling over the abdominal wall

http://ift.tt/2HiWxaK

Correction to: Voriconazole-induced periostitis deformans: serial imaging in a patient with ANCA vasculitis

Abstract

The original version of this paper unfortunately contained mistakes in the affiliations for all authors.

http://ift.tt/2GhfPvP

Not all sagittal band tears come with extensor instability: a case report with radiological and operative correlation

Abstract

The sagittal bands are a component of the extensor hood. They serve an important role in stabilizing the extensor tendon by forming a "check-rein" to radial–ulnar translation of the tendon over the metacarpal head, and extending the metacarpophalangeal (MCP) joint by virtue of attaching the extensor tendon to the palmar plate. Injury to the sagittal band is thought to cause extensor instability and subluxation to the contralateral side by disruption of this "check-rein" function, although recent evidence from cadaver studies suggests that ulnar sagittal band tear may be spared of extensor instability. As a case in point, we encountered a patient with surgically proven ulnar sagittal band tear, who did not have any extensor tendon subluxation or any limitation in motion. Intraoperative findings demonstrated a chronic-appearing ulnar sagittal band tear, indicating that chronic injury with fibrosis may stabilize the central band. Therefore, in patients with metacarpophalangeal pain without central tendon subluxation or limitation of motion, it remains important to raise the concern of sagittal band tear for appropriate treatment. We present the clinical course of this case, with radiological and operative findings, followed by a review of the relevant literature.

http://ift.tt/2HhxN2E

A child with painless left wrist swelling

http://ift.tt/2GfMD8n

Middle-aged female with palpable swelling over the abdominal wall

http://ift.tt/2Gg4gVK

Parosteal extra-axial chordoma of the second metacarpal bone: a case report with literature review

Abstract

Extra-axial chordoma is a chordoma that occurs in non-axial locations. It is a very rare tumor, with 20 cases reported to date; 14 in bone and six in soft tissue. Of the 14 skeletal extra-axial chordomas, ten were intramedullary and four were intracortical. We report the first case of parosteal extra-axial chordoma arising in the second metacarpal bone, expressing brachyury on immunohistochemical analysis, and describe the pathologic and radiologic findings. We suggest that extra-axial chordoma can occur in parosteal bone lesions or the hand, without features of bone distribution or bone-specific sites.

http://ift.tt/2HfOGdQ

A child with painless left wrist swelling

http://ift.tt/2HfOD1E

Lipoma arborescens of the bicipitoradial bursa

Abstract

Lipoma arborescens (LA) is a rare, benign articular lesion that is most commonly found within the suprapatellar recess of the knee. An extremely rare case of LA involving unilateral bicipitoradial bursa is described in this study. A 58-year-old male presented with a superficial soft mass on the volar aspect of the left forearm. The magnetic resonance imaging (MRI) examination demonstrated a lobulated complex mass containing multiple frond-like fatty nodules, along the distal biceps tendon in the bicipitoradial bursa. Ultrasound-guided biopsy of the lesion confirmed the diagnosis of LA and patient was scheduled for surgical excision. Recognizing the characteristic imaging of LA, particularly on MRI, is essential for accurate pre-procedural diagnosis.

http://ift.tt/2HeTkZP

Symptomatic os talus secundarius: a case report and review of the literature

Abstract

Os talus secundarius is an extremely rare accessory ossicle located at the lateral aspect of the talus just anterior to the fibula. Although rarely seen, it may cause lateral-sided chronic ankle pain. Only a few cases of symptomatic os talus secundarius have been reported to date. Herein, a 42-year-old male patient with symptomatic os talus secundarius is presented, and its imaging findings, differential diagnosis, and treatment are discussed.

Level of evidence: Level IV.

http://ift.tt/2Hki6b2

The predictive value of MRI in the syndesmotic instability of ankle fracture

Abstract

Objective

Although many types of ankle fracture can be combined with syndesmosis injury, preoperative imaging studies rarely reveal instability of the syndesmosis. This study assessed the use of magnetic resonance imaging (MRI) for syndesmotic instability in patients with unstable ankle fracture.

Methods

A total of 74 patients who were treated for Lauge-Hansen supination external rotation/Weber B type fracture or pronation external rotation/Weber C type fracture and who underwent MRI for preoperative assessment were enrolled. The MRI findings of the syndesmotic ligament and the results of an intraoperative stress test were evaluated.

Results

Twenty-six patients had a positive result on the intraoperative stress test for syndesmotic instability. The MRI findings of the syndesmotic ligaments revealed that complete tear of the posterior inferior tibiofibular ligament (PITFL) was the most reliable predictor of syndesmotic instability (sensitivity, 74%; specificity, 78%; positive predictive value, 54%). Interobserver agreement for the intraoperative stress test and MRI assessment was excellent, except for the MRI findings of the interosseous ligament (62% agreement; kappa, 0.3).

Conclusions

Complete tear of the PITFL on MRI has additional diagnostic value for syndesmotic instability in ankle fracture. However, because the sensitivity might not be sufficient to justify the costs associated with MRI, cost-effectiveness should be considered.

http://ift.tt/2Gg3WGw

Triple elastofibromas located in the supra- and infrascapular regions—a case report

Abstract

We report a case of triple elastofibromas located in the supra- and infrascapular regions. A 61-year-old female with a history of bilateral elastofibroma in the typical subscapular region (6 years before) was admitted for the evaluation of a left-sided suprascapular mass that she had first noted 3 months before. On physical examination, a firm, painless, mobile mass was palpated in the subcutaneous tissue. The patient had not observed any changes of the two known lesions over the past 6 years. The patient denied a family history of elastofibroma. The signal characteristic on T1- and T2-weighted images as well as contrast enhancement curves on dynamic study was identical in all three masses. Ultrasound-guided biopsy performed before surgical intervention confirmed the diagnosis of elastofibroma. This case report has a teaching value as, to our knowledge, it is the only one in the literature with images of synchronous elastofibromas documented by dynamic contrast-enhanced MRI. In cases of elastofibroma with diagnostic difficulties, particularly in uncommon sites, a dynamic contrast-enhanced MRI may help to establish the proper diagnosis. This case report gives an example of rare multiple elastofibromas, presents current diagnostic imaging methods, and reminds us that elastofibroma is not exclusive to the posterior thoracic region.

http://ift.tt/2Hgzi0S

Gastric cancer metastatic to neck lipoma: a case report with imaging consideration

Abstract

A 71-year-old man visited our hospital for examination of a soft neck mass. Computed tomography and magnetic resonance imaging scans showed a well-circumscribed large lipomatous tumor with multiple nodules inside. Atypical lipomatous tumor or lipoma involving the lymph nodes was considered. Pathological examination of the surgical specimen suggested typical lipoma including multiple metastatic foci from gastric cancer. Subsequent endoscopy revealed a gastric tumor, which was histologically proven to be signet-ring cell carcinoma. Considering these findings, this case was diagnosed as tumor-to-tumor metastasis to lipoma. We present the first such case with imaging and clinical characteristics.

http://ift.tt/2Gg3QPa

Percutaneous CT-guided sacroiliac joint sampling for infection: aspiration, biopsy, and technique

Abstract

Objective

To evaluate methods of CT-guided sacroiliac joint sampling in patients with suspected infection.

Materials and methods

All CT-guided sacroiliac joint sampling procedures for suspected infection were reviewed for sampling type (aspiration, lavage aspiration, biopsy), microbiology results, and clinical and imaging follow-up. The primary gold standard was anatomic pathology. If pathology was not available, then positive blood culture with the same organism as SIJ sampling, imaging and clinical follow-up, or clinical follow-up only were used. Anterior and posterior joint distention was evaluated by MRI within 7 days of the procedure.

Results

A total of 34 patients (age 39 ± 20 (range, 6–75) years; 21 F, 13 M) were included. Aspiration samples only were obtained in 13/34 (38%) cases, biopsy samples only in 9/34 (26%) cases, and both samples in 12/34 (35%) cases. There was an overall 54% sensitivity and 86% specificity. For the aspiration samples, sensitivity and specificity were 60 and 81%, respectively, compared to 45 and 90% for the biopsy samples. In cases with both samples, biopsy did not add additional microbial information. Seventeen (17/34, 50%) patients had an MRI. The anterior joint was more distended than the posterior joint in 15/17 (88%) of patients, and this difference was significant (P = 0.0003). All of these 17 patients had an attempted aspiration by a posterior approach; 6/17 (35%) resulted in a successful aspiration.

Conclusions

Aspiration of the sacroiliac joint has a higher sensitivity than biopsy and should always be attempted first. MRI may be helpful for procedure planning.

http://ift.tt/2HhGVEp

Complete resolution and remodeling of chronic recurrent multifocal osteomyelitis on MRI and radiographs

Abstract

Chronic recurrent multifocal osteomyelitis (CRMO) is a rare condition thought to be under-diagnosed, with a true prevalence of more than the 1 in 10,000 estimated. It is a condition that is classically described as polyostotic with a relapsing and remitting course, preferentially affecting the metaphyses of tubular bones in the pediatric population. Lesions have characteristic appearances of cortical hyperostosis and mixed lytic/sclerotic medullary appearances radiographically, with active osteitis and periostitis best seen with fluid-sensitive sequences on magnetic resonance imaging (MRI). There are reports of lesions resolving on follow-up radiographs and MRI scans, but no supporting images. In particular, although the marrow appearances and degree of osteitis have been shown to improve on MRI, complete resolution and remodeling back to normal has never been demonstrated. We present a case of a lesion that has completely healed and remodeled back to normal appearances on both radiographs and MRI, and consider this the standard for the often loosely used terms "normalization" and "resolution". We discuss the implications of this for our understanding of the natural history of CRMO, and how this adds weight to the condition being significantly under-diagnosed. It provides a "gold standard" to be aimed for when assessing treatments for CRMO, and the optimal outcomes that are possible. It also provides further insight into the potential of pediatric bone to recover and remodel when affected by inflammatory conditions.

http://ift.tt/2GgbGrP

Concomitant hook of hamate fractures in patients with scaphoid fracture: more common than you might think

Abstract

Objective

The scaphoid is the most commonly fractured carpal bone. The presence of a concomitant hook of hamate fracture is of particular relevance given that it is often occult on routine wrist/scaphoid radiographs and that hook of hamate fractures are prone to symptomatic non-union, resulting in chronic ulnar wrist pain. Prompt diagnosis and immobilisation/fixation may minimise such complications. Our study is aimed at assessing the frequency of concomitant hook of hamate fractures in patients with scaphoid fractures.

Methods

Hook of hamate fracture is often occult on wrist/scaphoid radiographs. Hence, we identified all 2,568 CT and MRI studies performed to investigate scaphoid fracture at our institution from April 2005 to March 2016. Three hundred and twelve out of 2,568 cases were confirmed to have a scaphoid fracture. Images were then retrospectively reviewed by a Consultant Musculoskeletal Radiologist and Musculoskeletal Radiologist Trainee to assess for the presence of concomitant hook of hamate fracture and, if present, whether this was identified on initial reporting.

Results

Concomitant hook of hamate fracture was identified in 10.3% of cases (32 out of 312, 30 on CT, 2 on MRI); most were minimally/non-displaced. Sixty percent of fractures identified on CT were missed on the initial review (18 out of 30). Both cases identified on MRI had been initially reported.

Conclusion

Scaphoid fracture is associated with higher than expected rates of concomitant hook of hamate fracture. Given the potential morbidity associated with hook of hamate fracture, this should be considered a review area when investigating scaphoid injury. These fractures are often minimally displaced, hence easily overlooked on CT. MRI may therefore be superior when investigating radiographically occult scaphoid fractures.

http://ift.tt/2HksxeG

Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor

Summary

Abrogating tumor angiogenesis by inhibiting vascular endothelial growth factor receptor-2 (VEGFR2) has been established as a therapeutic strategy for treating cancer. However, because of their low selectivity, most small molecule inhibitors of VEGFR2 tyrosine kinase exhibit unexpected adverse effects and limited anti-cancer efficacy. In this study, we detailed the pharmacologic properties of anlotinib, a highly potent and selective VEGFR2 inhibitor, in preclinical models. Anlotinib occupied the ATP-binding pocket of the VEGFR2 tyrosine kinase and showed high selectivity and inhibitory potency (IC₅₀ < 1 nM) for VEGFR2 relative to other tyrosine kinases. Concordant with this activity, anlotinib inhibited VEGF-induced signaling and cell proliferation in HUVECs with picomolar IC₅₀ values. However, micromolar concentrations of anlotinib were required to inhibit tumor cell proliferation directly in vitro. Anlotinib significantly inhibited HUVEC migration and tube formation; it also inhibited microvessel growth from explants of rat aorta in vitro and decreased vascular density in tumor tissue in vivo. Compared with the well-known tyrosine kinase inhibitor sunitinib, once-daily oral administration of anlotinib exhibited broader and stronger in vivo antitumor efficacy, and in some models, caused tumor regression in nude mice. Collectively, these results indicate that anlotinib is a well-tolerated, orally active VEGFR2 inhibitor that targets angiogenesis in tumor growth, and support ongoing clinical evaluation of anlotinib for a variety of malignancies.

This article is protected by copyright. All rights reserved.

http://ift.tt/2sBibUo

Overexpression of IL-35 in intrahepatic cholangiocarcinoma isa prognostic indicator after curative resection

Summary

Interleukin-35 (IL-35) is implicated in tumorigenesis, but the exact impact on intrahepatic cholangiocarcinoma (ICC) is not clearly. The aim of present study was to explore the specific effect of IL-35 on patient prognosis. Additionally, we formulated an effective prognostic nomogram for ICC patients after curative resection. Immunohistochemistry (IHC) was applied to explore IL-35 expression as well as IL-35R in 102 ICC patients. The results showed IL-35 was highly expressed in ICC tumor tissues and was positively associated with lymph node metastasis, TNM stage and vascular invasion and was independent prognostic factor for patients' OS and RFS. High expression of IL-35R (gp130 and IL-12Rβ2) were also observed in ICC cancer tissues, but only gp130 was independent prognostic factor for OS and RFS and indispensable in IL-35-mediated ICC clinical prognosis. The nomogram comprising CEA, lymph node metastasis, IL-35 and gp130 expression achieved better predictive accuracy compared with TNM stage for OS. Our data support that high IL-35 expression correlates with ICC aggressiveness and emerges as a valuable biomarker for evaluating ICC progression and prognosis in clinical work.

This article is protected by copyright. All rights reserved.

http://ift.tt/2C0b1N8

Left frontal hub connectivity delays cognitive impairment in autosomal-dominant and sporadic Alzheimer’s disease

Abstract

Patients with Alzheimer's disease vary in their ability to sustain cognitive abilities in the presence of brain pathology. A major open question is which brain mechanisms may support higher reserve capacity, i.e. relatively high cognitive performance at a given level of Alzheimer's pathology. Higher functional MRI-assessed functional connectivity of a hub in the left frontal cortex is a core candidate brain mechanism underlying reserve as it is associated with education (i.e. a protective factor often associated with higher reserve) and attenuated cognitive impairment in prodromal Alzheimer's disease. However, no study has yet assessed whether such hub connectivity of the left frontal cortex supports reserve throughout the evolution of pathological brain changes in Alzheimer's disease, including the presymptomatic stage when cognitive decline is subtle. To address this research gap, we obtained cross-sectional resting state functional MRI in 74 participants with autosomal dominant Alzheimer's disease, 55 controls from the Dominantly Inherited Alzheimer's Network and 75 amyloid-positive elderly participants, as well as 41 amyloid-negative cognitively normal elderly subjects from the German Center of Neurodegenerative Diseases multicentre study on biomarkers in sporadic Alzheimer's disease. For each participant, global left frontal cortex connectivity was computed as the average resting state functional connectivity between the left frontal cortex (seed) and each voxel in the grey matter. As a marker of disease stage, we applied estimated years from symptom onset in autosomal dominantly inherited Alzheimer's disease and cerebrospinal fluid tau levels in sporadic Alzheimer's disease cases. In both autosomal dominant and sporadic Alzheimer's disease patients, higher levels of left frontal cortex connectivity were correlated with greater education. For autosomal dominant Alzheimer's disease, a significant left frontal cortex connectivity × estimated years of onset interaction was found, indicating slower decline of memory and global cognition at higher levels of connectivity. Similarly, in sporadic amyloid-positive elderly subjects, the effect of tau on cognition was attenuated at higher levels of left frontal cortex connectivity. Polynomial regression analysis showed that the trajectory of cognitive decline was shifted towards a later stage of Alzheimer's disease in patients with higher levels of left frontal cortex connectivity. Together, our findings suggest that higher resilience against the development of cognitive impairment throughout the early stages of Alzheimer's disease is at least partially attributable to higher left frontal cortex-hub connectivity.

http://ift.tt/2C0eoUf

Intensity-Modulated Radiotherapy Triggers Onset of Bullous Pemphigoid in a Patient with Advanced Melanoma Treated with Nivolumab

Since the efficacy of ipilimumab on nivolumab-resistant advanced melanoma is extremely low, additional supportive therapy for anti-PD-1 antibody therapy-resistant advanced melanoma is needed. Although several supportive therapies that enhance the antitumor immune response of anti-PD-1 antibodies have already been reported, unexpected immune-related adverse events were detected at the same time. In this report, we describe a patient with advanced melanoma treated with nivolumab followed by intensity-modulated radiotherapy, which might have triggered bullous pemphigoid (BP). Although several cases of BP developing in anti-PD-1 antibody-treated patients have already been reported, in this report, we shed light on the possible pathogenesis of BP developing in a patient treated with nivolumab through M2 macrophages.
Case Rep Oncol 2018;11:114–118

http://ift.tt/2o6JKiQ

Multiloculated Cavitary Primary Pulmonary Hodgkin Lymphoma: Case Series

Primary pulmonary Hodgkin lymphoma (PPHL) is very rare and typically involves the superior portion of the lung. Pulmonary involvement is observed in 15–40% of Hodgkin lymphoma patients. Three such patients who presented with an unusual form of PPHL in radiological studies, i.e., multiloculated cavitary lesions, were admitted to our hospital. These lesions represent a new pathological and radiological feature of PPHL.
Case Rep Oncol 2018;11:90–97

http://ift.tt/2EI4RCf

A Randomized Trial of Mometasone Furoate 0.1% to Reduce High Grade Acute Radiation Dermatitis in Breast Cancer Patients Receiving Postmastectomy Radiation

A two-arm, double-blinded randomized trial was conducted to evaluate the efficacy of 0.1% mometasone furoate (MF) vs Eucerin Original® (E) cream in preventing the development of moderate to severe acute radiation dermatitis (ARD) in breast cancer patients receiving postmastectomy radiation (PMRT).

http://ift.tt/2F7GtrK

Impact of spot size and spacing on the quality of robustly-optimized intensity-modulated proton therapy plans for lung cancer

To investigate how spot size and spacing affect plan quality, robustness and interplay effects of robustly optimized intensity-modulated proton therapy (IMPT) for lung cancer.

http://ift.tt/2ErCFQP

Improved overall survival of mice by reducing lung side effects after high precision heart irradiation using SARRP

In radiotherapy of thoracal tumors parts of the heart and lung are often included in the radiation field. As a consequence, patients harbor an increased risk of developing radiation induced heart (RIHD) and lung diseases (RILD). There is clinical evidence that RIHD and RILD synergistically increase morbidity. This problem has also been observed in preclinical studies on RIHD in mice. The aim of this study was to reduce radiation exposure of the lung in experimental models to increase overall survival of mice to study late RIHD.

http://ift.tt/2F3QKFh

De novo variants in Myelin regulatory factor (MYRF) as candidates of a new syndrome of cardiac and urogenital anomalies

Myelin Regulatory Factor (MYRF) is a transcription factor that has previously been associated with the control of the expression of myelin-related genes. However, it is highly expressed in human tissues and mouse embryonic tissues outside the nervous system such as the stomach, lung, and small intestine. It has not previously been reported as a cause of any Mendelian disease. We report here two males with Scimitar syndrome [MIM 106700], and other features including penoscrotal hypospadias, cryptorchidism, pulmonary hypoplasia, tracheal anomalies, congenital diaphragmatic hernia, cleft spleen, thymic involution, and thyroid fibrosis. Gross neurologic functioning appears to be within normal limits. In both individuals a de novo variant in MYRF was identified using exome sequencing. Neither variant is found in gnomAD. Heterozygous variants in MYRF should be considered in patients with variants of Scimitar syndrome and urogenital anomalies.

http://ift.tt/2Cmlsq8

Gratitude, protective buffering, and cognitive dissonance: How families respond to pediatric whole exome sequencing in the absence of actionable results

Clinical genome and exome sequencing (CGES) may identify variants leading to targeted management of existing conditions. Yet, CGES often fails to identify pathogenic diagnostic variants and introduces uncertainties by detecting variants of uncertain significance (VUS) and secondary findings. This study investigated how families understand findings and adjust their perspectives on CGES. As part of NIH's Clinical Sequencing Exploratory Research Consortium, children were recruited from clinics at the Children's Hospital of Pennsylvania (CHOP) and offered exome sequencing. Primary pathogenic and possibly pathogenic, and some secondary findings were returned. Investigators digitally recorded results disclosure sessions and conducted 3-month follow up interviews with 10 adolescents and a parent. An interdisciplinary team coded all transcripts. Participants were initially disappointed with findings, yet reactions evolved within disclosure sessions and at 3-month interviews toward acceptance and satisfaction. Families erroneously expected, and prepared extensively, to learn about risk for common conditions. During disclosure sessions, parents and adolescents varied in how they monitored and responded to each others reactions. Several misinterpreted, or overestimated, the utility of findings to attribute meaning and achieve closure for the CGES experience. Participants perceived testing as an opportunity to improve disease management despite results that did not introduce new treatments or diagnoses. Future research may examine whether families experience cognitive dissonance regarding discrepancies between expectations and findings, and how protective buffering minimizes the burden of disappointment on loved ones. As CGES is increasingly integrated into clinical care providers must contend with tempering family expectations and interpretations of findings while managing complex medical care.

http://ift.tt/2Ewcw7L