Radiopaque drug-eluting embolisation beads as fiducial markers for stereotactic liver radiotherapy

OBJECTIVE: To determine the feasibility of using radiopaque (RO) beads as direct tumour surrogates for image-guided radiotherapy (IGRT) in patients with liver tumours after transarterial chemoembolisation (TACE). METHODS: A novel vandetanib-eluting RO bead was delivered via TACE as part of a first-in-human clinical trial in patients with either hepatocellular carcinoma or liver metastases from colorectal cancer. Following TACE, patients underwent simulated radiotherapy imaging with 4-dimensional computed tomography (4D-CT) and cone-beam CT (CBCT) imaging. RO beads were contoured using automated thresholding, and feasibility of matching between the simulated radiotherapy planning dataset (AVE-IP image from 4D data) and CBCT scans assessed. Additional kV, MV, helical CT and CBCT images of RO beads were obtained using an in-house phantom. Stability of RO bead position was assessed by comparing 4D-CT imaging to CT scans taken 6-20 days following TACE. RESULTS: Eight patients were treated and 4D-CT and CBCT images acquired. RO beads were visible on 4D-CT and CBCT images in all cases and matching successfully performed. Differences in centre of mass of RO beads between CBCT and simulated radiotherapy planning scans (AVE-IP dataset) were: 2.0 mm mediolaterally, 1.7 mm anteroposteriorally, 3.5 mm craniocaudally. RO beads in the phantom were visible on all imaging modalities assessed. RO bead position remained stable up to 29 days post-TACE. CONCLUSION: RO beads are visible on IGRT imaging modalities, showing minimal artefact. They can be used for on-set matching with CBCT and remain stable over time. ADVANCES IN KNOWLEDGE: The role of RO beads as fiducial markers for stereotactic liver radiotherapy is feasible and warrants further exploration as a combination therapy approach

Bacterial isolates from blood cultures of children with suspected septicaemia in Calabar, Nigeria

BACKGROUND: Septicaemia is a common cause of morbidity and mortality among children in the developing world. This pattern has changed little in the past decade. Physical signs and symptoms, though useful in identifying possible cases have limited specificity. Definitive diagnosis is by bacteriologic culture of blood samples to identify organisms and establish antibiotic susceptibility. These results are usually not available promptly. Therefore a knowledge of epidemiologic and antimicribial susceptibility pattern of common pathogens is useful for prompt treatment of patients. This report highlights the pattern of bacterial isolates in our environment from a retrospective study of our patients' records. METHODS: One thousand, two hundred and one blood samples were analysed from children aged 0–15 years, admitted into the children's wards of the University of Calabar Teaching Hospital, Calabar, Nigeria with features suggesting septicaemia. Samples were collected under aseptic conditions and cultured for aerobic and anaerobic organisms. Isolates were identified using bacteriologic and biochemical methods and antibiotic sensitivity determined by agar diffusion method using standard antibiotic discs. RESULTS: Bacteria was isolated in 552 (48.9%) of samples with highest rates among newborns (271 : 50.8). The most frequent isolates were Staphylococcal aureus (48.7%) and Coliforms (23.4%). Results showed high susceptibilities to the Cephalosporins (Ceftriazone- 100%:83.2%, Cefuroxime-100%:76.5%) and Macrolides (Azithromycin-100%:92.9%) for S. aureus and coliforms respectively. This study underscores the importance of septicaemia as a common cause of febrile illness in children and provides information on common prevalent aetiologic agents and drug susceptibilities of the commonest pathogens. CONCLUSION: Staphylococcus aureus and coliforms were the leading causes of septicaemia in children in this locality, and the third generation cephalosporins and azithromycin were shown to be effective against these pathogens

VEROnA Protocol: A Pilot, Open-Label, Single-Arm, Phase 0, Window-of-Opportunity Study of Vandetanib-Eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies

BACKGROUND: Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients treated. Despite advances and technical refinements of TACE, including the introduction of drug-eluting beads-TACE, the clinical efficacy of TACE has not been optimized, and improved arterial therapies are required. OBJECTIVE: The primary objectives of the VEROnA study are to evaluate the safety and tolerability of vandetanib-eluting radiopaque embolic beads (BTG-002814) in patients with resectable liver malignancies and to determine concentrations of vandetanib and the N-desmethyl metabolite in plasma and resected liver following treatment with BTG-002814. METHODS: The VEROnA study is a first-in-human, open-label, single-arm, phase 0, window-of-opportunity study of BTG-002814 (containing 100 mg vandetanib) delivered transarterially, 7 to 21 days before surgery in patients with resectable liver malignancies. Eligible patients have a diagnosis of colorectal liver metastases, or HCC (Childs Pugh A), diagnosed histologically or radiologically, and are candidates for liver surgery. All patients are followed up for 28 days following surgery. Secondary objectives of this study are to evaluate the anatomical distribution of BTG-002814 on noncontrast-enhanced imaging, to evaluate histopathological features in the surgical specimen, and to assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging following treatment with BTG-002814. Exploratory objectives of this study are to study blood biomarkers with the potential to identify patients likely to respond to treatment and to correlate the distribution of BTG-002814 on imaging with pathology by 3-dimensional modeling. RESULTS: Enrollment for the study was completed in February 2019. Results of a planned interim analysis were reviewed by a safety committee after the first 3 patients completed follow-up. The recommendation of the committee was to continue the study without any changes to the dose or trial design, as there were no significant unexpected toxicities related to BTG-002814. CONCLUSIONS: The VEROnA study is studying the feasibility of administering BTG-002814 to optimize the use of this novel technology as liver-directed therapy for patients with primary and secondary liver cancer. TRIAL REGISTRATION: ClinicalTrial.gov NCT03291379; https://clinicaltrials.gov/ct2/show/NCT03291379. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/13696

The actin-bundling protein Fascin is overexpressed in inflammatory bowel disease and may be important in tissue repair

<b>Background</b> Fascin is associated with increased cell motility in colorectal tumours but is absent from the normal colonic epithelium. We examined the expression of fascin in inflammatory bowel disease (IBD) and its location at regions undergoing restitution and regeneration. Tissue repair is essential for disease remission and we sought to determine the effects of therapeutic modalities on fascin expression and function using an in vitro model.<p></p> <b>Methods</b> Immunohistochemistry was performed on colonic tissue from IBD patients to determine changes in fascin expression and distribution. A human colorectal epithelial cell line was treated with 5-aminosalicylate (a common treatment for IBD), or sodium butyrate to determine the effect on fascin expression and cell motility.<p></p> <b>Results</b> Fascin overexpression was observed in both ulcerative colitis and Crohn's colitis and expression correlated with disease severity. Immunoreactivity was more intense and widespread in Crohn's compared to ulcerative colitis. Interestingly, highly expressing foci were consistently observed at the edges of ulcers where flattened, motile epithelial cells are actively involved in restitution, and also in areas of mucosal regeneration. 5-aminosalicylate reduced fascin expression in colorectal epithelial cells and inhibited their motility. Conversely, sodium butyrate increased fascin expression and stimulated cell motility in the same cells.<p></p> <b>Conclusions</b> Our data shows that fascin is overexpressed in inflammatory bowel disease and its location is indicative of a role in tissue repair. Our in vitro studies show that different therapeutic modalities may have converse effects on fascin expression and may have significant consequences for disease remission and the clinical management of IBD

A scoping review of the implications of adult obesity in the delivery and acceptance of dental care.

Background Due to the increasing prevalence of obesity within the general population it is presumed that the prevalence of overweight and obese adults accessing dental services will also increase. For this reason dentists need to be aware of implications of managing such patients.Methods A scoping review was carried out. Both Medline via OVID and Scopus databases were searched along with grey literature databases and the websites of key organizations. Inclusion and exclusion criteria were established. The data were collected on a purpose-made data collection form and analysed descriptively.Results The review identified 28 relevant published articles and two relevant items of grey literature. Following review of this literature three themes relating to adult obesity in the delivery and acceptance of dental care emerged; clinical, service delivery and patient implications. The majority of the papers focused on the clinical implications.Conclusion On the topic of adult obesity and dental care, the majority of published and grey literature focuses on the clinical implications. Further research is needed on both the patients' perspectives of being overweight or obese and the delivery and acceptance of dental care and the service delivery implications

Newly established tumourigenic primary human colon cancer cell lines are sensitive to TRAIL-induced apoptosis in vitro and in vivo

Most data on the therapeutic potential of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) as well as resistance to FAS ligand (FASL) in colorectal cancer have come from in vitro studies using cell lines. To gain a clearer understanding about the susceptibility of patient tumours to TRAIL and FASL, we derived primary human cancer epithelial cells from colon cancer patients. Characterisation of primary cultures PAP60 and MIH55 determined their highly proliferating advantage, transforming capability and tumorigenicity in vitro and in vivo. Although FASL treatment appeared to cause little apoptosis only in the PAP60 primary culture, increased apoptosis independent of p53 was observed in both primary PAP60 and MIH55 and control cell lines Caco-2, HT29 and DLD-1 after treatment with SuperKiller TRAIL. Expression analysis of death receptors (DR) in the original parental tumours, the primary cultures before and after engraftment as well as the mouse xenografts, revealed a significant upregulation of both DR4 and DR5, which correlated to differences in sensitivity of the cells to TRAIL-induced apoptosis. Treating patient tumour xenograft/SCID mouse models with Killer TRAIL in vivo suppressed tumour growth. This is the first demonstration of TRAIL-induced apoptosis in characterised tumorigenic primary human cultures (in vitro) and antitumour activity in xenograft models (in vivo)

The benefits and risks of bacille Calmette-Guérin vaccination among infants at high risk for both tuberculosis and severe combined immunodeficiency: assessment by Markov model

BACKGROUND: Bacille Calmette-Guérin (BCG) vaccine is given to Canadian Aboriginal neonates in selected communities. Severe reactions and deaths associated with BCG have been reported among infants born with immunodeficiency syndromes. The main objective of this study was to estimate threshold values for severe combined immunodeficiency (SCID) incidence, above which BCG is associated with greater risk than benefit. METHODS: A Markov model was developed to simulate the natural histories of tuberculosis (TB) and SCID in children from birth to 14 years. The annual risk of tuberculous infection (ARI) and SCID incidence were varied in analyses. The model compared a scenario of no vaccination to intervention with BCG. Appropriate variability and uncertainty analyses were conducted. Outcomes included TB incidence and quality-adjusted life years (QALYs). RESULTS: In sensitivity analyses, QALYs were lower among vaccinated infants if the ARI was 0.1% and the rate of SCID was higher than 4.2 per 100,000. Assuming an ARI of 1%, this threshold increased to 41 per 100,000. In uncertainty analyses (Monte Carlo simulations) which assumed an ARI of 0.1%, QALYs were not significantly increased by BCG unless SCID incidence is 0. With this ARI, QALYs were significantly decreased among vaccinated children if SCID incidence exceeds 23 per 100,000. BCG is associated with a significant increase in QALYs if the ARI is 1%, and SCID incidence is below 5 per 100,000. CONCLUSION: The possibility that Canadian Aboriginal children are at increased risk for SCID has serious implications for continued BCG use in this population. In this context, enhanced TB Control – including early detection and treatment of infection – may be a safer, more effective alternative

Expression of G protein-coupled receptors and related proteins in HEK293, AtT20, BV2, and N18 cell lines as revealed by microarray analysis

<p>Abstract</p> <p>Background</p> <p>G protein coupled receptors (GPCRs) are one of the most widely studied gene superfamilies. Thousands of GPCR research studies have utilized heterologous expression systems such as human embryonic kidney cells (HEK293). Though often treated as 'blank slates', these cell lines nevertheless endogenously express GPCRs and related signaling proteins. The outcome of a given GPCR study can be profoundly influenced by this largely unknown complement of receptors and/or signaling proteins. Little easily accessible information exists that describes the expression profiles of the GPCRs in cell lines. What is accessible is often limited in scope - of the hundreds of GPCRs and related proteins, one is unlikely to find information on expression of more than a dozen proteins in a given cell line. Microarray technology has allowed rapid analysis of mRNA levels of thousands of candidate genes, but though often publicly available, the results can be difficult to efficiently access or even to interpret.</p> <p>Results</p> <p>To bridge this gap, we have used microarrays to measure the mRNA levels of a comprehensive profile of non-chemosensory GPCRs and over a hundred GPCR signaling related gene products in four cell lines frequently used for GPCR research: HEK293, AtT20, BV2, and N18.</p> <p>Conclusions</p> <p>This study provides researchers an easily accessible mRNA profile of the endogenous signaling repertoire that these four cell lines possess. This will assist in choosing the most appropriate cell line for studying GPCRs and related signaling proteins. It also provides a better understanding of the potential interactions between GPCRs and those signaling proteins.</p

The effectiveness and cost-effectiveness of strength and balance Exergames to reduce falls risk for people aged 55 years and older in UK assisted living facilities: A multi-centre, cluster randomised controlled trial

Background: Falls are the leading cause of fatal and non-fatal unintentional injuries in older people. The use of Exergames (active, gamified video-based exercises) is a possible innovative, community-based approach. This study aimed to determine the effectiveness of a tailored OTAGO/FaME based strength and balance Exergame programme for improving balance, maintaining function and reducing falls risk in older people. Methods: A two-arm cluster randomised controlled trial recruiting adults aged 55 years and older living in 18 assisted-living (sheltered housing) facilities (clusters) in the UK. Standard care (physiotherapy advice and leaflet) was compared to a tailored 12-week strength and balance Exergame programme, supported by physiotherapists or trained assistants. Complete-case analysis (intention to treat) was used to compare Berg Balance Scale (BBS) at baseline and at 12 weeks. Secondary outcomes included: fear of falling, mobility, falls risk, pain, mood, fatigue, cognition, healthcare utilisation and health-related quality of life; self-reported physical activity and falls. Results: Eighteen clusters were randomised (9 to each arm) with 56 participants allocated to the intervention and 50 to the control (78% female, mean age 78 years). Fourteen participants withdrew over the 12 weeks (both arms), mainly for ill health. There was an adjusted mean improvement in balance (BBS) of 6.2 (95% CI 2.4 to 10.0), reduced fear of falling (p=0.007) and pain (p=0.02) in Exergame group. Mean attendance at sessions was 69% (mean exercising time of 33 minutes/week). 24% of control group and 20% of Exergame group fell over trial period. The change in falls rates significantly favoured the intervention (incident rate ratio 0.31 (95% CI 0.16 to 0.62, p=0.001)). The point estimate of the incremental cost effectiveness ratio (ICER) was £15,209.80 per QALY. Using 10,000 bootstrap replications, at the lower bound of the NICE threshold of £20,000 per QALY, there was a 61% probability of Exergames being cost-effective, rising to 73% at the upper bound of £30,000 per QALY. Conclusions: Exergames, as delivered in this trial, improve balance, pain and fear of falling and are a cost-effective fall prevention strategy in assisted living facilities for people aged 55 years or older

Expression and function of G-protein-coupled receptorsin the male reproductive tract

This review focuses on the expression and function of muscarinic acetylcholine receptors (mAChRs), α1-adrenoceptors and relaxin receptors in the male reproductive tract. The localization and differential expression of mAChR and α1-adrenoceptor subtypes in specific compartments of the efferent ductules, epididymis, vas deferens, seminal vesicle and prostate of various species indicate a role for these receptors in the modulation of luminal fluid composition and smooth muscle contraction, including effects on male fertility. Furthermore, the activation of mAChRs induces transactivation of the epidermal growth factor receptor (EGFR) and the Sertoli cell proliferation. The relaxin receptors are present in the testis, RXFP1 in elongated spermatids and Sertoli cells from rat, and RXFP2 in Leydig and germ cells from rat and human, suggesting a role for these receptors in the spermatogenic process. The localization of both receptors in the apical portion of epithelial cells and smooth muscle layers of the vas deferens suggests an involvement of these receptors in the contraction and regulation of secretion.Esta revisão enfatiza a expressão e a função dos receptores muscarínicos, adrenoceptores α1 e receptores para relaxina no sistema reprodutor masculino. A expressão dos receptores muscarínicos e adrenoceptores α1 em compartimentos específicos de dúctulos eferentes, epidídimo, ductos deferentes, vesícula seminal e próstata de várias espécies indica o envolvimento destes receptores na modulação da composição do fluido luminal e na contração do músculo liso, incluindo efeitos na fertilidade masculina. Além disso, a ativação dos receptores muscarínicos leva à transativação do receptor para o fator crescimento epidermal e proliferação das células de Sertoli. Os receptores para relaxina estão presentes no testículo, RXFP1 nas espermátides alongadas e células de Sertoli de rato e RXFP2 nas células de Leydig e germinativas de ratos e humano, sugerindo o envolvimento destes receptores no processo espermatogênico. A localização de ambos os receptores na porção apical das células epiteliais e no músculo liso dos ductos deferentes de rato sugere um papel na contração e na regulação da secreção.Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)Universidade Federal de São Paulo (UNIFESP) Escola Paulista de Medicina Departamento de FarmacologiaUNIFESP, EPM, Depto. de FarmacologiaSciEL