Πέμπτη, 23 Φεβρουαρίου 2017

Cancers, Vol. 9, Pages 21: AR Signaling in Breast Cancer

Androgen receptor (AR, a member of the steroid hormone receptor family) status has become increasingly important as both a prognostic marker and potential therapeutic target in breast cancer. AR is expressed in up to 90% of estrogen receptor (ER) positive breast cancer, and to a lesser degree, human epidermal growth factor 2 (HER2) amplified tumors. In the former, AR signaling has been correlated with a better prognosis given its inhibitory activity in estrogen dependent disease, though conversely has also been shown to increase resistance to anti-estrogen therapies such as tamoxifen. AR blockade can mitigate this resistance, and thus serves as a potential target in ER-positive breast cancer. In HER2 amplified breast cancer, studies are somewhat conflicting, though most show either no effect or are associated with poorer survival. Much of the available data on AR signaling is in triple-negative breast cancer (TNBC), which is an aggressive disease with inferior outcomes comparative to other breast cancer subtypes. At present, there are no approved targeted therapies in TNBC, making study of the AR signaling pathway compelling. Gene expression profiling studies have also identified a luminal androgen receptor (LAR) subtype that is dependent on AR signaling in TNBC. Regardless, there seems to be an association between AR expression and improved outcomes in TNBC. Despite lower pathologic complete response (pCR) rates with neoadjuvant therapy, patients with AR-expressing TNBC have been shown to have a better prognosis than those that are AR-negative. Clinical studies targeting AR have shown somewhat promising results. In this paper we review the literature on the biology of AR in breast cancer and its prognostic and predictive roles. We also present our thoughts on therapeutic strategies.

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Surgeon input will boost CT lung cancer screening

2017_02_23_13_08_11_996_2017_02_24_ESTS_CT lung cancer screening is at the fore with 10 new recommendations from the...


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ContextVision to show upgraded software at ECR 2017

Image enhancement software developer ContextVision plans to highlight upgrades...


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Evaluation of impact of an external breast shield (FlexiShield) in electronic brachytherapy for breast IORT: A phantom study

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Publication date: Available online 23 February 2017
Source:Brachytherapy
Author(s): Yongbok Kim, Jason Wei-Yeong Huynh, Victor J. Gonzalez
PurposeTo investigate Axxent (iCAD, Inc., San Jose, CA) electronic brachytherapy balloon deformation and its dosimetric impact because of an external flexible shield (FlexiShield [FS]; iCAD, Inc.).Methods and MaterialsProstheses breast tissue phantom overlaid three spherical balloon applicators to simulate three clinical scenarios depending on minimum skin-to-balloon surface spacing (SS): balloon with SS of 2 cm, 1 cm, and balloon with 1 cm SS and touching the chest wall. Two sets of megavoltage CT (MVCT) scans were obtained with or without FS for 15 different sizes of balloons. For 45 pairs of MVCT scans, balloon deformation was measured in superior–inferior (dSI) dimension on coronal and sagittal planes and anterior–posterior (dAP) and lateral (dLAT) dimensions on the equatorial plane of balloon. SS was also compared. A treatment plan was made on each MVCT scan. Doses at four balloon surface points and skin were compared. Conformity index value was also compared to evaluate three-dimensional dose distribution. Clinically, 20 Gy was prescribed to the surface of balloon.ResultsBalloon deformation was observed with compression in SI and AP dimensions and expansion in lateral dimension. Average SI compression was 0.5 mm. Average dLat - dAP was 2.4 mm, which resulted in elevated point doses at AP dimension by 10.8% of prescribed dose and reduced point doses at lateral dimension by 4.6%. FS decreased SS by 1.8 mm, increasing skin dose by 1.2 Gy, on average. Conformity index value was decreased from 0.922 to 0.908, on average.ConclusionsThis phantom study demonstrates that use of skin shielding during breast intraoperative radiation therapy can cause balloon deformation and SS reduction, resulting in dosimetric changes that are disregarded in current practice.



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Prostate MRI for brachytherapists: Anatomy and technique

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Publication date: Available online 23 February 2017
Source:Brachytherapy
Author(s): A.M. Venkatesan, R.J. Stafford, C. Duran, P.D. Soni, A. Berlin, P.W. McLaughlin
PurposeTo present an overview of mp MRI techniques necessary for high-resolution imaging of prostate.MethodsWe summarize examples from our clinical experience and concepts from the current literature that illustrate normal prostate anatomy on multiparametric MRI (mp MRI).ResultsOur experience regarding optimal mp MRI image acquisition is provided, as well as a summary of prostate and periprostatic anatomy and anatomical variants that pose challenges for BT.Conclusionsmp MRI provides unparalleled assessment of the prostate and periprostatic anatomy, making it the most appropriate imaging modality to facilitate prostate BT treatment planning, implantation, and followup. This work provides an introduction to prostate mp MR imaging, anatomy, and anatomical variants essential for successful integration mp MRI into prostate brachytherapy practice.



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Tetralogy of Fallot

Tetralogy of Fallot: A combination of four heart defects that are present at birth and account for about 10 percent of all congenital heart disease:

  • Ventricular septal defect (VSD)A hole between the two bottom chambers, the ventricles, of the heart that permits oxygen-poor blood from the right ventricle to mix with oxygen-rich blood from the left ventricle.
  • Pulmonary stenosisNarrowing of the outlet to the pulmonary artery area with an abnormal pulmonary valve impeding blood flow from the right ventricle to the lungs.
  • Right ventricular hypertrophy (RVH)Thickening and enlargement of the muscle of the right ventricle.
  • Overriding aortaA case in which the aorta overrides or straddles the wall (the septum) between the ventricles, permitting oxygen-poor blood to flow through the VSD into the aorta.

Open-heart surgery is done on patients with tetralogy of Fallot in infancy or early childhood. Untreated tetralogy of Fallot is usually fatal before age 20. With open-heart surgery, the patient has an excellent chance of survival.



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Studies in Late Antiquity

Studies in Late Antiquity, published by University of California Press, last updated on 2017-02-23, available at http://sla.ucpress.edu

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Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance [Research]

Hepatic insulin resistance and hepatosteatosis in diet-induced obesity are associated with various metabolic diseases, yet the underlying mechanisms remain to be fully elucidated. Here we show that the expression levels of the disulfide-bond A oxidoreductase-like protein (DsbA-L) are significantly reduced in the liver of obese mice and humans. Liver-specific knockout or adenovirus-mediated overexpression of DsbA-L exacerbates or alleviates, respectively, high-fat diet–induced mitochondrial dysfunction, hepatosteatosis, and insulin resistance in mice. Mechanistically, we found that DsbA-L is localized in mitochondria and that its deficiency is associated with impairment of maximum respiratory capacity, elevated cellular oxidative stress, and increased JNK activity. Our results identify DsbA-L as a critical regulator of mitochondrial function, and its down-regulation in the liver may contribute to obesity-induced hepatosteatosis and whole body insulin resistance.—Chen, H., Bai, J., Dong, F., Fang, H., Zhang, Y., Meng, W., Liu, B., Luo, Y., Liu, M., Bai, Y., Abdul-Ghani, M. A., Li, R., Wu, J., Zeng, R., Zhou, Z., Dong, L. Q., Liu, F. Hepatic DsbA-L protects mice from diet-induced hepatosteatosis and insulin resistance.



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Heat shock protein 27-derived atheroprotection involves reverse cholesterol transport that is dependent on GM-CSF to maintain ABCA1 and ABCG1 expression in ApoE-/- mice [Research]

Recently, we demonstrated that heat shock protein (HSP)-27 is protective against the development of experimental atherosclerosis, reducing plaque cholesterol content by more than 30%. Moreover, elevated HSP-27 levels are predictive of relative freedom from clinical cardiovascular events. HSP-27 signaling occurs via the activation of NF-B which induces a marked up-regulation in GM-CSF expression, a cytokine that is known to alter ABC transporters involved in reverse cholesterol transport (RCT). Therefore, we hypothesized that HSP-27-derived GM-CSF has a potent role in impeding plaque formation by promoting macrophage RCT and sought to better characterize this pathway. Treatment of THP-1 cells, RAW-Blue cells, and primary macrophages with recombinant HSP-27 resulted in NF-B activation via TLR-4 and was inhibited by various pharmacologic blockers of this pathway. Moreover, HSP-27-induced upregulation of GM-CSF expression was dependent on TLR-4 signaling. recombinant (r)HSP-27 treatment of ApoE–/– female (but not male) mice for 4 wk yielded reductions in plaque area and cholesterol clefts of 33 and 47%, respectively, with no effect on GM-CSF–/–ApoE–/– mice. With 12 wk of rHSP-27 treatment, both female and male mice showed reductions in plaque burden (55 and 42%, respectively) and a 60% reduction in necrotic core area but no treatment effect in GM-CSF–/–ApoE–/– mice. In vitro functional studies revealed that HSP-27 enhanced the expression of ABCA1 and ABCG1, as well as facilitated cholesterol efflux in vitro by ~10%. These novel findings establish a paradigm for HSP-27-mediated RCT and set the stage for the development of HSP-27 atheroprotective therapeutics.—Pulakazhi Venu, V. K., Adijiang, A., Seibert, T., Chen, Y.-X., Shi, C., Batulan, Z., O’Brien, E. R. Heat shock protein 27–derived atheroprotection involves reverse cholesterol transport that is dependent on GM-CSF to maintain ABCA1 and ABCG1 expression in ApoE–/– mice.



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Der physiologische und der pathologische Schluckvorgang

Zusammenfassung

In Deutschland leiden derzeit schätzungsweise 5 Mio. Menschen an einer Schluckstörung. Diese Zahl wird voraussichtlich aufgrund der längeren Lebenserwartung, aber auch durch das vermehrte Überleben von extrem Frühgeborenen noch zunehmen. Diagnostisch wird ausgehend von den 4 Schluckphasen zunächst analysiert, ob ein anatomisch-organisches oder ein funktionelles Hindernis vorliegt. Dazu gehört die Erhebung einer ausführlichen Anamnese und die Untersuchung der Hirnnervenfunktionen, des orofazialen Bereichs, der Schluckreflexe, des pharyngealen und des ösophagealen Transportwegs. Es wird auf altersabhängige Variationen des Schluckvorgangs, nasale Regurgitation, Retentionen im Zungengrund und Hypopharynx oder Anzeichnen für eine Aspiration geachtet.



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Alveolar Macrophages in Allergic Asthma: the Forgotten Cell Awakes

Abstract

Purpose of Review

The role of alveolar macrophages in innate immune responses has long been appreciated. Here, we review recent studies evaluating the participation of these cells in allergic inflammation.

Recent Findings

Immediately after allergen exposure, monocytes are rapidly recruited from the bloodstream and serve to promote acute inflammation. By contrast, resident alveolar macrophages play a predominantly suppressive role in an effort to restore homeostasis. As inflammation becomes established after repeated exposures, alveolar macrophages can polarize across a continuum of activation phenotypes, losing their suppressive functions and gaining pathogenic functions.

Summary

Future research should focus on the diverse roles of monocytes/macrophages during various types and phases of allergic inflammation. These properties could lead us to new therapeutic opportunities.



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Phenotype-Driven Therapeutics in Severe Asthma

Abstract

Inhaled corticosteroids are the mainstay of asthma treatment using a step-up approach with incremental dosing and additional controller medications in order to achieve symptom control and prevent exacerbations. While most patients respond well to this treatment approach, some patients remain refractory despite high doses of inhaled corticosteroids and a long-acting β-agonist. The problem lies in the heterogeneity of severe asthma, which is further supported by the emergence of severe asthma phenotypes. This heterogeneity contributes to the variability in treatment response. Randomized controlled trials involving add-on therapies in poorly controlled asthma have challenged the idea of a “one size fits all” approach targeting specific phenotypes in their subject selection. This review discusses severe asthma phenotypes from unbiased clustering approaches and the most recent scientific evidence on novel treatments to provide a guide in personalizing severe asthma treatment.



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Contemporary Use of Corticosteroids in Rhinology

Abstract

Purpose of Review

Exogenously administered corticosteroids are widely used today in the field of rhinology. Allergic rhinitis (AR), non-allergic rhinitis (NAR), acute rhinosinusitis (ARS), chronic rhinosinusitis with (CRSwNP) and without (CRSsNP) nasal polyps, and autoimmune disorders with nasal manifestations are common diseases treated effectively with intranasal and oral glucocorticoids. We focus on physiological pathways, therapeutic benefits, indications, contra-indications, and side effects of glucocorticoid utilization in the treatment of rhinologic disorders such as AR, NAR, ARS, CRSsNP, and CRSwNP.

Recent Findings

Second-generation intranasal steroid (INS) agents have pharmacokinetic characteristics that minimize their systemic bioavailability, resulting in minimum risk for systemic adverse events. Several studies have demonstrated the symptomatic efficacy of both intranasal and oral corticosteroids in ARS. Moreover, intranasal and systemic steroid administration has been repeatedly proven beneficial in the conservative and perioperative management of CRSwNP. For patients with AR, there is no need for oral steroids, with the exception of severe cases, as there is lack of superiority to INS. SCUAD patients challenge currently available treatment schemes, underlining the importance of research in the field.

Summary

Corticosteroids’ effectiveness in the treatment of various rhinologic disorders is indisputable. However, their characteristics, and potential side effects, make a clear consensus for utilization difficult.



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Effects of Allergic Sensitization on Antiviral Immunity: Allergen, Virus, and Host Cell Mechanisms

Abstract

Purpose of Review

Multiple clinical and epidemiological studies demonstrate links between allergic sensitization and virus-induced atopic disease exacerbations. This review summarizes the recent findings regarding allergen, viral, and host cellular mechanisms relevant to these observations.

Recent Findings

Recent studies have focused on the molecular pathways and genetic influences involved in allergen-mediated inhibition of innate antiviral immune responses. Multiple tissue and cell types from atopic individuals across the atopy spectrum exhibit deficient interferon responses to a variety of virus infections. Impairment in barrier function, viral RNA and DNA recognition by intracellular sensing molecules, and dysregulation of signaling components are broadly affected by allergic sensitization. Finally, genetic predisposition by numerous nucleotide polymorphisms also impacts immune pathways and potentially contributes to virus-associated atopic disease pathogenesis.

Summary

Allergen-virus interactions in the setting of atopy involve complex tissue and cellular mechanisms. Future studies defining the pathways underlying these interactions could uncover potential therapeutic targets. Available data suggest that therapies tailored to restore specific components of antiviral responses will likely lead to improved clinical outcomes in allergic disease.



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Comparison of digital panoramic radiography versus cone beam computerized tomography for measuring alveolar bone

Cone beam computerized tomography (CBCT) has been widely used in dental implanting. However, the local hospitals usually don’t have access to CBCT due to the cost and medical investment, especially in West of ...

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IJERPH, Vol. 14, Pages 222: High Prevalence and Genetic Polymorphisms of Legionella in Natural and Man-Made Aquatic Environments in Wenzhou, China

Natural and engineered water systems are the main sources of Legionnaires’ disease. It is essential from a public health perspective to survey water environments for the existence of Legionella. To analyze the main serogroups, genotypes and pathogenicity of the pathogen, a stratified sampling method was adopted to collect water samples randomly from shower water, cooling tower water, and local public hot springs in Wenzhou, China. Suspected strains were isolated from concentrated water samples. Serum agglutination assay and real-time PCR (Polymerase chain reaction) were used to identify L. pneumophila. Sequence-based typing (SBT) and pulsed-field gel electrophoresis (PFGE) were used to elucidate the genetic polymorphisms in the collected isolates. The intracellular growth ability of the isolates was determined through their interaction with J774 cells and plating them onto BCYE (Buffered Charcoal Yeast Extract) agar plates. Overall, 25.56% (46/180) of water samples were Legionella-positive; fifty-two strains were isolated and two kinds of serogroups were co-detected from six water samples from 2015 to 2016. Bacterial concentrations ranged from 20 CFU/100 mL to 10,720 CFU/100 mL. In detail, the Legionella-positive rates of shower water, cooling tower water and hot springs water were 15.45%, 13.33%, and 62.5%, respectively. The main serogroups were LP1 (30.69%) and LP3 (28.85%) and all strains carried the dot gene. Among them, 52 isolates and another 10 former isolates were analyzed by PFGE. Nineteen distinct patterns were observed in 52 strains isolated from 2015 to 2016 with three patterns being observed in 10 strains isolated from 2009 to 2014. Seventy-three strains containing 52 from this study and 21 former isolates were selected for SBT analysis and divided into 25 different sequence types in 4 main clonal groups belonging to 4 homomorphic types. Ten strains were chosen to show their abilities to grow and multiply in J744 cells. Taken together, our results demonstrate a high prevalence and genetic polymorphism of Legionella in Wenzhou’s environmental water system. The investigated environmental water sources pose a potential threat to the public where intervention could help to prevent the occurrence of Legionnaires’ disease.

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Age-Friendliness and Life Satisfaction of Young-Old and Old-Old in Hong Kong

Age-friendliness, promoted by the World Health Organization (WHO), aims to enable and support individuals in different aspects of life for fostering life satisfaction and personal well-being as they age. We identified specific aspect(s) of age-friendliness associated with life satisfaction and examined similarities and differences in age-friendliness and life satisfaction in young-old and old-old adults. Six hundred and eighty-two ageing adults were asked to complete a survey questionnaire consisting of the Age-friendly City Scale, Satisfaction with Life Scale, and sociodemographic variables. Multiple linear regression analysis was used to examine the effects of various domains of age-friendliness on life satisfaction among the young-old adults (aged 65 to 74, ) and the old-old adults (aged 75 to 97, ). Common domains associated with life satisfaction in both young-old and old-old groups were transportation and social participation. Community and health services were associated with life satisfaction for the young-old group only. On the other hand, civic participation and employment was significantly associated with the old-old group only. Social participation is important for the young-old and the old-old. Ageing older adults can be a resource to the society. Implications for promoting and implementing age-friendliness were discussed in the context of successful and productive ageing and the need for a more refined taxonomy of social activities.

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GAMBLINGLESS: FOR LIFE study protocol: a pragmatic randomised trial of an online cognitive-behavioural programme for disordered gambling

Introduction

The prevalence of disordered gambling worldwide has been estimated at 2.3%. Only a small minority of disordered gamblers seek specialist face-to-face treatment, and so a need for alternative treatment delivery models that capitalise on advances in communication technology, and use self-directed activity that can complement existing services has been identified. As such, the primary aim of this study is to evaluate an online self-directed cognitive–behavioural programme for disordered gambling (GamblingLess: For Life).

Methods and analysis

The study will be a 2-arm, parallel group, pragmatic randomised trial. Participants will be randomly allocated to a pure self-directed (PSD) or guided self-directed (GSD) intervention. Participants in both groups will be asked to work through the 4 modules of the GamblingLess programme over 8 weeks. Participants in the GSD intervention will also receive weekly emails of guidance and support from a gambling counsellor. A total of 200 participants will be recruited. Participants will be eligible if they reside in Australia, are aged 18 years and over, have access to the internet, have adequate knowledge of the English language, are seeking help for their own gambling problems and are willing to take part in the intervention and associated assessments. Assessments will be conducted at preintervention, and at 2, 3 and 12 months from preintervention. The primary outcome is gambling severity, assessed using the Gambling Symptom Assessment Scale. Secondary outcomes include gambling frequency, gambling expenditure, psychological distress, quality of life and additional help-seeking. Qualitative interviews will also be conducted with a subsample of participants and the Guides (counsellors).

Ethics and dissemination

The study has been approved by the Deakin University Human Research and Eastern Health Human Research Ethics Committees. Findings will be disseminated via report, peer-reviewed publications and conference presentations.

Trial registration number

ACTRN12615000864527; results.



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How does a physical activity programme in elementary school affect fracture risk? A prospective controlled intervention study in Malmo, Sweden

Objectives

Recent evidence from the 7-year follow-up of the Pediatric Osteoporosis Prevention (POP) study indicates an inverse correlation between years of participation in a physical activity (PA) intervention and fracture risk in children. However, we could not see a statistically significant reduction in fracture risk, which urged for an extension of the intervention.

Setting

The study was conducted in 4 neighbouring elementary schools, where 1 school functioned as intervention school.

Participants

We included all children who began first grade in these 4 schools between 1998 and 2012. This resulted in 1339 children in the intervention group and 2195 children in the control group, all aged 6–8 years at the state of the study.

Intervention

We launched an 8-year intervention programme with 40 min of moderate PA per school day, while the controls continued with the Swedish national standard of 60 min of PA per week.

Primary outcome measure

We used the regional radiographic archive to register objectively verified fractures and we estimated annual fracture incidences and incidence rate ratios (IRRs).

Results

During the first year after initiation of the intervention, the fracture IRR was 1.65 (1.05 to 2.08) (mean 95% CI). For each year of the study, the fracture incidence rate in the control group compared with the intervention group increased by 15.7% (5.6% to 26.8%) (mean 95% CI). After 8 years, the IRR of fractures was 52% lower in the intervention group than in the control group (IRR 0.48 (0.25 to 0.91) (mean 95% CI))].

Conclusions

Introduction of the school-based intervention programme is associated with a higher fracture risk in the intervention group during the first year followed by a gradual reduction, so that during the eighth year, the fracture risk was lower in the intervention group.

Trial registration number

NCT00633828.



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Advanced Practice Nursing Competency Assessment Instrument (APNCAI): clinimetric validation

Objective

To describe the development and clinimetric validation of the Advanced Practice Nursing Competency Assessment Instrument (APNCAI) through several evidence sources about reliability and validity in the Spanish context.

Design and setting

APNCAI development was based on a multisequential and systematic process: literature review, instrument content consensus through qualitative Delphi method approach (a panel of 51 Advanced Practice in Nursing –APN– experts was selected) and the clinimetric validation process based on a sample of 600 nurses from the Balearic Islands public healthcare setting.

Methods

An initial step for tool's content development process based on Delphi method approach of expert consensus was implemented. A subsequent phase of tool validation started from the analysis of APN core competencies latent measurement model, including exploratory and confirmatory techniques. Reliability evidence for each latent factor was also obtained. Items' scores were submitted to descriptive analysis, plus univariate and multivariate normality tests.

Results

An eight-factor competency assessment latent model obtained adequate fit, and it was composed by ‘Research and Evidence-Based Practice’, ‘Clinical and Professional Leadership’, ‘Interprofessional Relationship and Mentoring’, ‘Professional Autonomy’, ‘Quality Management’, ‘Care Management’, ‘Professional Teaching and Education’ and ‘Health Promotion’.

Conclusions

Adequate empirical evidence of reliability and validity for APNCAI makes it useful for application in healthcare policy programmes for APN competency assessment in Spain.



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Electronic nicotine delivery systems and/or electronic non-nicotine delivery systems for tobacco smoking cessation or reduction: a systematic review and meta-analysis

Objective

A systematic review and meta-analysis to investigate the impact of electronic nicotine delivery systems (ENDS) and/or electronic non-nicotine delivery systems (ENNDS) versus no smoking cessation aid, or alternative smoking cessation aids, in cigarette smokers on long-term tobacco use.

Data sources

Searches of MEDLINE, EMBASE, PsycInfo, CINAHL, CENTRAL and Web of Science up to December 2015.

Study selection

Randomised controlled trials (RCTs) and prospective cohort studies.

Data extraction

Three pairs of reviewers independently screened potentially eligible articles, extracted data from included studies on populations, interventions and outcomes and assessed their risk of bias. We used the Grading of Recommendations Assessment, Development and Evaluation approach to rate overall certainty of the evidence by outcome.

Data synthesis

Three randomised trials including 1007 participants and nine cohorts including 13 115 participants proved eligible. Results provided by only two RCTs suggest a possible increase in tobacco smoking cessation with ENDS in comparison with ENNDS (RR 2.03, 95% CI 0.94 to 4.38; p=0.07; I2=0%, risk difference (RD) 64/1000 over 6 to 12 months, low-certainty evidence). Results from cohort studies suggested a possible reduction in quit rates with use of ENDS compared with no use of ENDS (OR 0.74, 95% CI 0.55 to 1.00; p=0.051; I2=56%, very low certainty).

Conclusions

There is very limited evidence regarding the impact of ENDS or ENNDS on tobacco smoking cessation, reduction or adverse effects: data from RCTs are of low certainty and observational studies of very low certainty. The limitations of the cohort studies led us to a rating of very low-certainty evidence from which no credible inferences can be drawn. Lack of usefulness with regard to address the question of e-cigarettes' efficacy on smoking reduction and cessation was largely due to poor reporting. This review underlines the need to conduct well-designed trials measuring biochemically validated outcomes and adverse effects.



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Outcomes associated with prescribed medications in older adults with multimorbidity: protocol for a scoping review

Introduction

Multimorbidity becomes increasingly prevalent with ageing. Polypharmacy is often associated with multimorbidity because patients accrue medications to treat each individual disease; however, there is uncertainty around the generalisability of disease-specific guidelines. Namely, the extrapolation of results from studies conducted in younger patients to older adults with multimorbidity. The main objective of this scoping review is to explore our current knowledge of the outcomes that older adults with multimorbidity experience from taking prescribed medications.

Methods and analysis

A scoping review will be conducted to explore what is known about the outcomes experienced by older adults with multimorbidity who are taking guideline-recommended medications and to identify areas for future research. In addition to searching the grey literature, the following databases will be searched from 1990 onward: MEDLINE, EMBASE, PsycINFO and the Cochrane Library. Experimental, quasi-experimental and non-experimental studies consisting of patients ≥65 years old who have two or more comorbid conditions (explicitly grouped together for the purpose of analysis) and who are being prescribed a guideline-recommended prescription medication for a chronic condition will be considered for inclusion in our scoping review. We will describe patient (eg, mortality, morbidity, quality of life) and health system (eg, number of emergency department visits or hospitalisations, cost to third-party payer) outcomes associated with the prescription of medications for older adults who have two or more chronic comorbid conditions. Two reviewers will complete all screening and data abstraction independently. Data will be synthesised with descriptive statistics.

Ethics and dissemination

Ethics approval is not required because this is a scoping review of published literature. Results will be disseminated through conference presentations and publication in a peer-reviewed journal.



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Inter-rater reliability between nurses for a new paediatric triage system based primarily on vital parameters: the Paediatric Triage Instrument (PETI)

Introduction

The major paediatric triage systems are primarily based on flow charts involving signs and symptoms for orientation and subjective estimates of the patient's condition. In contrast, the 4-level Paediatric Triage Instrument (PETI) is primarily based on vital parameters and was developed exclusively for paediatric triage in patients with medical symptoms. The aim of this study was to assess the inter-rater reliability of this triage system in children when used by nurses.

Methods

A design was employed in which triage was performed simultaneously and independently by a research nurse and an emergency department (ED) nurse using the PETI. All patients aged ≤12 years who presented at the ED with a medical symptom were considered eligible for participation.

Results

The 89 participants exhibited a median age of 2 years and were triaged by 28 different nurses. The inter-rater reliability between nurses calculated with the quadratic-weighted was 0.78 (95% CI 0.67 to 0.89); the linear-weighted was 0.67 (95% CI 0.56 to 0.80) and the unweighted was 0.59 (95% CI 0.44 to 0.73). For the patients aged <1, 1–3 and >3 years, the quadratic-weighted values were 0.67 (95% CI 0.39 to 0.94), 0.86 (95% CI 0.75 to 0.97) and 0.73 (95% CI 0.49 to 0.97), respectively. The median triage duration was 6 min.

Conclusions

The PETI exhibited substantial reliability when used in children aged ≤12 years and almost perfect reliability among children aged 1–3 years. Moreover, rapid application of the PETI was demonstrated. This study has some limitations, including sample size and generalisability, but the PETI exhibited promise regarding reliability, and the next step could be either a larger reliability study or a validation study.



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Fatigue and its associated factors in liver transplant recipients in Beijing: a cross-sectional study

Objectives

Fatigue is a highly prevalent symptom experienced by patients who underwent the liver transplantation. However, the influencing factors of fatigue are poorly understood by healthcare professionals. The aim of this study was to examine the intensity, interference, duration and prevalence of fatigue in liver transplantation recipients and to explore the influencing factors of post-transplantation fatigue.

Design

A cross-sectional design was used in this study.

Methods

A convenience sample of liver transplant recipients was recruited at an outpatient transplant clinic of a general hospital in Beijing, China. Self-report survey data were provided by liver transplant recipients using the Fatigue Symptom Inventory (FSI), the Hospital Anxiety and Depression Scale (HADS), the Perceived Social Support Scale (PSSS) and the Athens Insomnia Scale (AIS). Demographic, clinical and psychosocial parameters were evaluated as fatigue influencing factors.

Results

Participants (n=285) included 69 women and 216 men. Fatigue was found in 87.0% of liver transplant recipients. Mean scores of fatigue intensity items were 4.47±2.85, 1.93±1.97, 3.15±2.13 and 2.73±2.42 (most fatigue, least fatigue, average fatigue in the week prior to assessment and fatigue at the point of assessment). The mean score of fatigue interference was 2.27±2.09.The number of days fatigued in the week prior to assessment was 2.26±2.02 and the amount of time fatigued each day was 2.75±2.44. Spearman's correlation analysis showed that fatigue intensity was positively associated with anxiety, depression and insomnia (p<0.001 for all), while fatigue interference was positively associated with gender, anxiety, depression and insomnia (p<0.05 for all). In the multiple linear regression analysis, anxiety and insomnia were positively associated with fatigue intensity (p<0.001), and insomnia, depression and anxiety were positively associated with fatigue interference (p<0.001).

Conclusions

Fatigue is common in liver transplant recipients, and it is strongly associated with insomnia, anxiety and depression.



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Social disadvantages associated with myasthenia gravis and its treatment: a multicentre cross-sectional study

Objectives

To clarify the social disadvantages associated with myasthenia gravis (MG) and examine associations with its disease and treatment.

Design

Cross-sectional study.

Setting and participants

We evaluated 917 consecutive cases of established MG seen at 13 neurological centres in Japan over a short duration.

Outcome measures

All patients completed a questionnaire on social disadvantages resulting from MG and its treatment and a 15-item MG-specific quality of life scale at study entry. Clinical severity at the worst condition was graded according to the MG Foundation of America classification, and that at the current condition was determined according to the quantitative MG score and MG composite. Maximum dose and duration of dose ≥20 mg/day of oral prednisolone during the disease course were obtained from the patients' medical records. Achievement of the treatment target (minimal manifestation status with prednisolone at ≤5 mg/day) was determined at 1, 2 and 4 years after starting treatment and at study entry.

Results

We found that 27.2% of the patients had experienced unemployment, 4.1% had been unwillingly transferred and 35.9% had experienced a decrease in income, 47.1% of whom reported that the decrease was ≥50% of their previous total income. In addition, 49.0% of the patients reported feeling reduced social positivity. Factors promoting social disadvantages were severity of illness, dose and duration of prednisolone, long-term treatment, and a depressive state and change in appearance after treatment with oral steroids. Early achievement of the treatment target was a major inhibiting factor.

Conclusions

Patients with MG often experience unemployment, unwilling job transfers and a decrease in income. In addition, many patients report feeling reduced social positivity. To inhibit the social disadvantages associated with MG and its treatment, greater focus needs to be placed on helping patients with MG resume a normal lifestyle as soon as possible by achieving the treatment target.



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Role of ethnicity in human papillomavirus vaccination uptake: a cross-sectional study of girls from ethnic minority groups attending London schools

Objectives

Research suggests that girls from ethnic minority groups are less likely to receive the human papillomavirus (HPV) vaccination than white British girls; however, the specific ethnic minority groups that have lower uptake have not been identified. This study aimed to examine the relationship between school-level uptake and ethnicity as well as uptake and other ethnicity-related factors, to understand which specific groups are less likely to receive the vaccination.

Methods

Aggregated uptake rates from 195 schools were obtained for each of the three recommended vaccine doses from 2008 to 2010. Census data at the lower super output area (LSOA) level for the postcode of each school were also obtained, describing the ethnic breakdown of the resident population (ethnicity, language spoken, religion, proficiency in English and duration of residency in the UK). These were used as proxy measures of the ethnic make-up of the schools. The most prevalent non-majority group for each ethnicity and ethnicity-related factor was assigned to each school. Analyses explored differences in uptake by ethnicity and ethnicity-related factors.

Results

No significant differences in vaccination uptake were found by ethnicity or ethnicity-related factors, although descriptive differences were apparent. Schools in areas where black ethnicities were the most prevalent non-white British ethnicities had consistently low rates of uptake for all doses. Schools in areas where some Asian ethnicities were the most prevalent non-white British ethnicities had consistently high rates of uptake for all doses. There was evidence of variability in mean uptake rates for ethnicities within ‘black’ and ‘Asian’ ethnic groups.

Conclusions

Future research would benefit from focusing on specific ethnicities rather than broad ethnic categories. Replication of this study with a larger sample and using complete individual-level data, collected on a national level, would provide a clearer indication of where ethnic differences in HPV vaccination uptake exist.



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How do organisational characteristics influence teamwork and service delivery in lung cancer diagnostic assessment programmes? A mixed-methods study

Objectives

Diagnostic assessment programmes (DAPs) can reduce wait times for cancer diagnosis, but optimal DAP design is unknown. This study explored how organisational characteristics influenced multidisciplinary teamwork and diagnostic service delivery in lung cancer DAPs.

Design

A mixed-methods approach integrated data from descriptive qualitative interviews and medical record abstraction at 4 lung cancer DAPs. Findings were analysed with the Integrated Team Effectiveness Model.

Setting

4 DAPs at 2 teaching and 2 community hospitals in Canada.

Participants

22 staff were interviewed about organisational characteristics, target service benchmarks, and teamwork processes, determinants and outcomes; 314 medical records were reviewed for actual service benchmarks.

Results

Formal, informal and asynchronous team processes enabled service delivery and yielded many perceived benefits at the patient, staff and service levels. However, several DAP characteristics challenged teamwork and service delivery: referral volume/workload, time since launch, days per week of operation, rural–remote population, number and type of full-time/part-time human resources, staff colocation, information systems. As a result, all sites failed to meet target benchmarks (from referral to consultation median 4.0 visits, median wait time 35.0 days). Recommendations included improved information systems, more staff in all specialties, staff colocation and expanded roles for patient navigators. Findings were captured in a conceptual framework of lung cancer DAP teamwork determinants and outcomes.

Conclusions

This study identified several DAP characteristics that could be improved to facilitate teamwork and enhance service delivery, thereby contributing to knowledge of organisational determinants of teamwork and associated outcomes. Findings can be used to update existing DAP guidelines, and by managers to plan or evaluate lung cancer DAPs. Ongoing research is needed to identify ideal roles for navigators, and staffing models tailored to case volumes.



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Internet-based cognitive-behavioural writing therapy for reducing post-traumatic stress after intensive care for sepsis in patients and their spouses (REPAIR): study protocol for a randomised-controlled trial

Introduction

As a consequence of sepsis and intensive care, considerable proportions of patients but also of their spouses develop a post-traumatic stress disorder (PTSD). However, only a very small number receive psychotherapeutic treatment. Internet-based cognitive–behavioural writing therapy (IB-CBWT) has proven to be an effective treatment option for PTSD. It seems to fit the specific needs of this cohort and to overcome treatment barriers. Aim of the REPAIR trial is to examine the efficacy, safety and applicability of IB-CBWT for PTSD in patients and their spouses after intensive care for sepsis.

Methods and analysis

Participants will be assigned randomly either to a treatment or a wait-list (WL) control group. The treatment group receives IB-CBWT for PTSD, actively involving the partners of the participants. IB-CBWT will be guided by a therapist and comprises two written assignments per week over a 5 week period. After completing the assignments, the participants obtain individual responses from the therapist. Participants of the WL control group will receive treatment after a waiting period of 5 weeks. The primary outcome is PTSD symptom severity in self-rated PTSD Checklist for Diagnostic and Statistical Manual Fifth Edition at the end of treatment and waiting time, respectively. Secondary outcomes are remission of PTSD, depression, anxiety, and somatisation measured by the Brief Symptom Inventory-18, marital satisfaction measured by the Relationship Assessment Scale, health-related quality of life measured by the EQ-5D-5L, and the feasibility of IB-CBWT for this cohort (ie, dropout rate). Statistical analysis will be performed according to the intent-to-treat principle.

Ethics and dissemination

The study is conducted according to the principles of Good Clinical Practice and has been approved by the ethics committee of the Friedrich-Schiller University Jena, Germany. Results will be disseminated at scientific conferences, published in peer-reviewed journals, and provided to consumers of healthcare.

Trial registration number

Pre-results, DRKS00010676.



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Factors influencing medical students' motivation to practise in rural areas in low-income and middle-income countries: a systematic review

Objectives

There is a shortage of doctors working in rural areas all over the world, especially in low-income and middle-income countries. The choice to practise medicine in a rural area is influenced by many factors. Motivation developed as a medical student is one key determinant of this choice. This study explores influences on medical students' motivation to practise in rural areas of low-income and middle-income countries following graduation.

Design

A systematic review was conducted to identify influences on medical students' motivation to work in rural areas in low-income and middle-income countries. Papers reporting influences on motivation were included, and content analysis was conducted to select the articles. Articles not published in English were excluded from this review.

Results

A rural background (ie, being brought up in a rural area), training in rural areas with a community-based curriculum, early exposure to the community during medical training and rural location of medical school motivate medical students to work in rural areas. Perceived lack of infrastructure, high workload, poor hospital management and isolation are among the health facility factors that demotivate medical students for medical practice in rural areas.

Conclusions

Medical school selection criteria focusing on a rural background factor and medical education curriculum focusing on rural area are more relevant factors in low-income and middle-income countries. The factors identified in this review may assist the planners, medical educators and policymakers in low-income and middle-income countries in designing relevant interventions to positively influence rural choices where the shortage of rural physicians is an ongoing and increasing concern.



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Gene expression profiling in persons with multiple chemical sensitivity before and after a controlled n-butanol exposure session

Objectives

To investigate the pathophysiological pathways leading to symptoms elicitation in multiple chemical sensitivity (MCS) by comparing gene expression in MCS participants and healthy controls before and after a chemical exposure optimised to cause symptoms among MCS participants.

The first hypothesis was that unexposed and symptom-free MCS participants have similar gene expression patterns to controls and a second hypothesis that MCS participants can be separated from controls based on differential gene expression upon a controlled n-butanol exposure.

Design

Participants were exposed to 3.7 ppm n-butanol while seated in a windowed exposure chamber for 60 min. A total of 26 genes involved in biochemical pathways found in the literature have been proposed to play a role in the pathogenesis of MCS and other functional somatic syndromes were selected. Expression levels were compared between MCS and controls before, within 15 min after being exposed to and 4 hours after the exposure.

Settings

Participants suffering from MCS and healthy controls were recruited through advertisement at public places and in a local newspaper.

Participants

36 participants who considered themselves sensitive were prescreened for eligibility. 18 sensitive persons fulfilling the criteria for MCS were enrolled together with 18 healthy controls.

Outcome measures

17 genes showed sufficient transcriptional level for analysis. Group comparisons were conducted for each gene at the 3 times points and for the computed area under the curve (AUC) expression levels.

Results

MCS participants and controls displayed similar gene expression levels both at baseline and after the exposure and the computed AUC values were likewise comparable between the 2 groups. The intragroup variation in expression levels among MCS participants was noticeably greater than the controls.

Conclusions

MCS participants and controls have similar gene expression levels at baseline and it was not possible to separate MCS participants from controls based on gene expression measured after the exposure.



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Characteristics and prognoses of patients treated by an anaesthesiologist-manned prehospital emergency care unit. A retrospective cohort study

Objective

When planning and dimensioning an emergency medical system, knowledge of the population serviced is vital. The amount of literature concerning the prehospital population is sparse. In order to add to the current body of literature regarding prehospital treatment, thus aiding future public health planning, we describe the workload of a prehospital anaesthesiologist-manned mobile emergency care unit (MECU) and the total population it services in terms of factors associated with mortality.

Participants

The study is a register-based study investigating all missions carried out by a MECU operating in a mixed urban/rural area in Denmark from 1 May 2006 to 31 December 2014. Information on missions was extracted from the local MECU registry and linked at the individual level to the Danish population-based databases, the National Patient Registry and the Civil Registration System.

Primary and secondary outcome measures

Primary outcome measures were number of missions and number of patient contacts. Secondary patient variables were mortality and association between mortality and age, sex, comorbidity, prior admission to hospital and response time.

Results

The MECU completed 41 513 missions (mean 13.1 missions/day) having 32 873 patient contacts, corresponding to 19.2 missions and 15.2 patient encounters per 1000 patient years. Patient variables: the median age was 57 years (range 0–108 years), 42.8% (42.3% to 43.4%) were women. For patients admitted to hospital alive, 30-day mortality was 5.7% (5.4% to 6.0%); 90-day mortality was 8.1% (7.8% to 8.5%) while 2-year mortality was 16.4% (16.0% to 16.8%). Increasing age, male sex, comorbidity and prior admission to hospital but not response time were associated with mortality.

Conclusions

Mortality following an incident requiring the assistance of a MECU was high in the first 2 years following the incident. MECU response time assessed as a continuous parameter was not associated with patient outcome.



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Looking back and to the future: Are we improving ‘cure’ in non-small cell lung cancer?

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): David Walder, Mary O'Brien
In surgical series, cancer-free survival at 5 years is often referred to as a cure. In recent years, attempts to improve cure rates in non-small cell lung cancer (NSCLC) have focussed on earlier diagnosis through cost-effective screening programs. Systemic therapies have historically added only a small benefit to overall survival in both the adjuvant and palliative setting. However, in the last two decades, the development of new treatment options has added incremental improvements in NSCLC survival rates. Patients with a targetable sensitising mutation including epidermal growth factor receptor gene mutations and anaplastic lymphoma kinase rearrangements have significantly better prognosis, and many will survive beyond 5 years. Immunotherapy is an effective treatment in selected patients with NSCLC and is set to cause another leap in 5 year survival rates. Although these patients are not free from disease, survival at 5 years may become the more important end-point as NSCLC becomes seen as a chronic oncological disease.



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Surgically treated oesophageal cancer developed in a radiated field: Impact on peri-operative and long-term outcomes

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Sheraz R. Markar, Caroline Gronnier, Arnaud Pasquer, Alain Duhamel, Hélène Behal, Jérémie Théreaux, Johan Gagnière, Gil Lebreton, Cécile Brigand, Bernard Meunier, Denis Collet, Christophe Mariette
BackgroundThe objectives of this study were to compare peri-operative and long-term outcomes from oesophageal cancer (EC) (i) that arose in a previously radiated field (ECRF) versus primary (PEC) and among ECRF patients and (ii) radiotherapy-induced (RIEC) versus non-radiotherapy–induced EC (NRIEC).MethodsData were collected from 30 European centres from 2000 to 2010. Two thousand four hundred eighty nine EC patients surgically treated were included in the PEC group and 136 in the ECRF group, NRIEC group (n = 61) and RIEC group (n = 75). Propensity score matching analyses were used to compensate for differences in baseline characteristics.ResultsCompared to the PEC group, the ECRF group was characterised by less use of neoadjuvant chemoradiotherapy (0% versus 29.5%; P < 0.001), less pathological stage III/IV (31.6% versus 39.2%, P = 0.036), greater incidence of R1/2 margins (21.3% versus 10.9%; P < 0.001), increased in-hospital mortality (14.0% versus 7.1%; P = 0.003) and overall morbidity (68.4% versus 56.4%, P = 0.006). After matching, 5-year overall (28.8% versus 50.5%; hazard ratio [HR] = 1.53, 95% confidence interval [CI]: 1.15–2.04; P = 0.003) and event-free (32.2% versus 42.5%; HR = 1.56, 95% CI: 1.18–2.05; P = 0.002) survivals were significantly reduced in the ECRF group. There were no significant differences in incidence or pattern of tumour recurrence. Comparing RIEC and NRIEC groups, there were no significant differences in short- or long-term outcomes before and after matching.ConclusionsECRF is associated with poorer long-term survival related to a reduced utilisation of neoadjuvant chemoradiotherapy and an increased incidence of tumour margin involvement at surgery. Outcomes appear to be dictated by the limitations related to previous radiotherapy administration more than the radiotherapy-induced carcinogenesis.



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Survival of patients with melanoma brain metastasis treated with stereotactic radiosurgery and active systemic drug therapies

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Ee Siang Choong, Serigne Lo, Martin Drummond, Gerald B. Fogarty, Alexander M. Menzies, Alexander Guminski, Brindha Shivalingam, Kathryn Clarke, Georgina V. Long, Angela M. Hong
IntroductionWith new systemic therapies demonstrating activity in melanoma brain metastasis, most of the previously reported stereotactic radiosurgery (SRS) data are superseded. In this study, we report the outcomes (overall survival [OS] and brain control [BC]) and identify factors that associate with such outcomes in the era of modern systemic therapy.MethodA total of 108 patients treated with SRS from 2010 to 2015 were included. Systemic treatment use within 6 weeks of SRS was noted. OS was defined as time from SRS to death or last follow-up, and BC was defined as absence of any active intracranial disease during follow-up. Univariate and multivariate Cox proportional hazard analyses were performed on clinico-pathological prognostic features associated with OS and BC.ResultsThe median age was 64.3 years, and the median follow-up was 8.6 months. Seventy-nine (73.1%) patients received systemic treatment. The median OS were as follows: anti-CTLA4 – 7.5 months (95% CI: 4.4–15.6), anti-PD1 – 20.4 months (95% CI: 8.8 – N/A) and BRAF inhibitor (BRAFi) ± MEK inhibitor (MEKi) – 17.8 months (95% CI: 11.8 – N/A). Median BC was as follows: anti-CTLA4 – 7.5 months (95% CI: 4.0–15.6), anti-PD1 – 12.7 months (95% CI: 5.5 – N/A) and BRAFi ± MEKi – 12.7 months (95% CI: 8.3–18.5). In multivariate analysis, age and type of systemic therapy were strongly associated with OS. Age, Eastern Cooperative Oncology Group performance status, Graded Prognostic Assessment (GPA) score, and presence of symptoms were associated with BC.ConclusionsFavourable outcomes are seen in patients treated with SRS and with the best survival seen in patients treated with anti-PD1. Known independent prognostic factors for survival such as age and performance status and GPA score remain relevant in this setting.



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The number of extranodal sites assessed by PET/CT scan is a powerful predictor of CNS relapse for patients with diffuse large B-cell lymphoma: An international multicenter study of 1532 patients treated with chemoimmunotherapy

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Tarec Christoffer El-Galaly, Diego Villa, Thomas Yssing Michaelsen, Martin Hutchings, Nabegh George Mikhaeel, Kerry J. Savage, Laurie H. Sehn, Sally Barrington, Jakob W. Hansen, Daniel Smith, Kirsty Rady, Karen J. Mylam, Thomas S. Larsen, Staffan Holmberg, Maja B. Juul, Sabrina Cordua, Michael R. Clausen, Kristina B. Jensen, Hans E. Johnsen, John F. Seymour, Joseph M. Connors, Peter de Nully Brown, Martin Bøgsted, Chan Y. Cheah
PurposeDevelopment of secondary central nervous system involvement (SCNS) in patients with diffuse large B-cell lymphoma is associated with poor outcomes. The CNS International Prognostic Index (CNS-IPI) has been proposed for identifying patients at greatest risk, but the optimal model is unknown.MethodsWe retrospectively analysed patients with diffuse large B-cell lymphoma diagnosed between 2001 and 2013, staged with PET/CT and treated with R-CHOP(-like) regimens. Baseline clinicopathologic characteristics, treatments, and outcome data were collected from clinical databases and medical files. We evaluated the association between candidate prognostic factors and modelled different risk models for predicting SCNS.ResultsOf 1532 patients, 62 (4%) subsequently developed SCNS. By multivariate analysis, disease stage III/IV, elevated serum LDH, kidney/adrenal and uterine/testicular involvement were independently associated with SCNS. There was a strong correlation between absolute number of extranodal sites and risk of SCNS; the 144 patients (9%) with >2 extranodal sites had a 3-year cumulative incidence of SCNS of 15.2% (95% confidence interval [CI] 9.2–21.2%) compared with 2.6% (95% CI 1.7–3.5) among those with ≤2 sites (P < 0.001). The 3-year cumulative risks of SCNS for CNS-IPI defined risk groups were 11.2%, 3.1% and 0.4% for high-, intermediate- and low-risk patients, respectively. All risk models analysed had high negative predictive values, but only modest positive predictive values.ConclusionsPatients with >2 extranodal sites or high-risk disease according to the CNS-IPI should be considered for baseline CNS staging. Clinical risk prediction models suffer from limited positive predictive ability, highlighting the need for more sensitive biomarkers to identify patients at highest risk of this devastating complication.



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Does axillary lymph node dissection impact survival in patients with breast cancer and isolated tumour cells or micrometastasis in sentinel node?

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): Mina M.G. Youssef, Diane Cameron, Sisse Olsen, Douglas Ferguson




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Letter to the Editor regarding the paper by Park et al., Extra-gain of HER2-positive cases through HER2 reassessment in primary and metastatic sites in advanced gastric cancer with initially HER2-negative primary tumours: Results of GASTric cancer HER2 reassessment study 1 (GASTHER1)

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Publication date: April 2017
Source:European Journal of Cancer, Volume 75
Author(s): A. Ieni, G. Angelico, P. Zeppa, G. Tuccari




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An avoidable cause of thymoglobulin anaphylaxis

Thymoglobulin® (anti-thymocyte globulin [rabbit]) is a purified pasteurised, gamma immune globulin obtained by immunisation of rabbits with human thymocytes. Anaphylactic allergic reactions to a first injectio...

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Alkaloid extracts from Combretum zeyheri inhibit the growth of Mycobacterium smegmatis

Current tuberculosis regimens have failed to combat the issue of drug resistance and ethno medicines may represent a possible source of antimycobacterial agents. Combretum species are well known in African tra...

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Chemical composition and pharmacological significance of Anethum Sowa L. Root

Medicinal herbs are used for the treatment of different ailments since antiquity. Different parts of Anethum sowa L. is used in folk medicine as a carminative for the treatment of flatulence, colic and hiccups of...

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Allium hookeri root extract exerts anti-inflammatory effects by nuclear factor-κB down-regulation in lipopolysaccharide-induced RAW264.7 cells

Allium hookeri (AH) is widely consumed as a vegetable and herbal medicine in southeastern Asia. AH has been reported antioxidant, antimicrobial, improvement of bone health and antidiab...

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Effects of mindfulness-based interventions on biomarkers in healthy and cancer populations: a systematic review

Only a small number of articles have investigated the relationship between mindfulness-based interventions (MBIs) and biomarkers. The aim of this systematic review was to study the effect of MBIs on specific b...

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Knowledge and Practices Relating to Acute Pesticide Poisoning Among Health Care Providers in Selected Regions of Tanzania

Background: Acute pesticide poisoning (APP) is commonly underdiagnosed in Tanzania. Studies in developing countries suggest that a lack of diagnostic skills among health care providers (HCPs) undermines surveillance for APP. This study aimed at characterizing experience and skills of Tanzanian HCPs regarding APP diagnosis and management. Methodology: The population included HCPs responsible for managing APP in Kilimanjaro and Arusha regions (n = 91). The resulting sample included 66 respondents (response rate: 73%). The data were collected in 2005 using a standardized questionnaire. Results: Half of all respondents (50%) reported handling at least 1 APP case with 15% reporting handling more than 5 cases in the past. Reported experience of handling an APP case was marginally higher in respondents who reported ⩾4 years of work experience in the health sector compared with those with <4 years of work experience (odds ratio = 1.32; 95% confidence interval = 0.9-1.5). Most of the respondents had high knowledge of exposure routes, reporting awareness of oral (98.5%), inhalational (93.9%), and dermal (77%) routes. The study revealed low awareness of pesticide classification by chemical groups (29%) or World Health Organization hazard (0%) and weak knowledge on pesticide label instructions (55%). Organophosphates accounted for 35% of the pesticide products reported by respondents as being responsible for poisoning. Some treatment options were incorrectly reported as first aid options, and some reported first aid options were wrong or inappropriate. Conclusions: The study revealed that HCPs in northern Tanzania lack adequate skills to diagnose and manage APP. For effective surveillance of APP, there is a need to include training on hazards, classification, diagnosis, and health effects in the training programmes for all HCPs in Tanzania.

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Self-reported Effects of Water on Health in First Nations Communities in Saskatchewan, Canada: Results From Community-Based Participatory Research

Water-related health challenges on First Nations reserves in Canada have been previously documented. Our objective was to describe factors associated with self-reported health effects from tap water in 8 First Nations reserve communities in Saskatchewan, Canada. Community-based participatory approaches were used in designing and implementing cross-sectional household surveys. Individual, household, community, and contextual effects were considered in multilevel analysis. Negative health effects from tap water were reported by 28% of households (n = 579). Concerns about environmental factors affecting water quality (odds ratio OR = 3.4, 95% confidence interval CI = 1.8-6.7), rarely or never drinking tap water (OR = 2.9, 95% CI = 1.3-6.6), insufficient tap water (OR = 3.0, 95% CI = 1.4-6.3), paying for bottled water (OR = 3.2, 95% CI = 1.2-8.7), and dissatisfaction with tap water were associated with self-reported health effects (n = 393); however, the effect of dissatisfaction was modified by respondent age (P = .03). Quality and availability were associated with perceptions of health effects from drinking water, providing additional information on how ongoing concerns about drinking water influence self-reported health in some First Nations.

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Diagnosis of drowning: Electrolytes and total protein in sphenoid sinus liquid

In forensic diagnosis, diagnosis of drowning presents a major problem [1]. Useful findings for diagnosis of drowning include the presence of micro-froth around the mouth and in the airways, pleural effusion, emphysema aquosum, water in the stomach and duodenum, and diatoms in the blood and various organs [1–9]. It is also important to determine whether drowning occurred in freshwater or seawater because it is important to determine the site where drowning occurred [1]. To determine whether drowning occurred in freshwater or seawater is greatly assisted by the characteristics of the lungs, diatom test, electrolyte concentration of the liquid in the stomach and duodenum, and electrolyte concentration of pleural effusion [1–5,10–14].

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Electrochemical impedance spectroscopy: a deeper and quantitative insight into the fingermarks physical modifications over time

Fingermarks found at the crime scene undoubtedly represent one of the most important forms of physical evidence of paramount forensic relevance. Although significant progresses have been achieved in recent years in the field of latent fingermarks development, as a result of astonishing advancements in the field of nanotechnology [1–4], as well as in immunological detection techniques [5–7], there is still increasingly need for enhancements in sensitivity and specificity, as recently underlined by several researchers [8,9], in order to reduce the number of fingermarks remaining undetected.

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Effect of hand sanitizer on the performance of fingermark detection techniques

Hand sanitizers are effective microbial killing liquids, gels or foams that are used to disinfect and cleanse hands without the need for soap and water. Hand sanitizers have been a growing commodity ever since their introduction in 1966, with hand sanitizer sales peaking to over 15 million sales in a single week in 2009–(coinciding with the news of a H1N1 outbreak) [1]. These products were originally alcohol-based, with ethanol or isopropanol as the active ingredient. At concentrations between 60 to 95 percent [2], alcohols are effective against most bacteria and fungi, and many viruses, killing these organisms by denaturing their proteins, dissolving their lipids, and subsequently interfering with their metabolism and cell lysis [3].

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Clinical Validation of a house dust mite environmental challenge chamber model

In this dust mite allergen challenge chamber model a reproducible correlation between allergen concentration and nasal symptoms has been demonstrated. Retest reproducibility of nasal symptoms measured by TNSS and decreased nasal flow quantified by RMM at three different occasions was demonstrated. Inter-chamber variability of nasal symptoms and nasal flow between two different chamber rooms (VCC 2 and VCC3) was determined to be 2.5% (SD 0.2%) and 3.3% (SD of 1.2 and 2.3) respectively. Chamber exposure in this model was safe in mite allergic subjects with controlled asthma.

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Can We Predict Fall Asthma Exacerbations? Validation Of The Seasonal Asthma Exacerbation Index

The saEPI and its individual components help identify children with asthma at high risk or low risk for a fall asthma exacerbation in the presence of guideline-based therapy with and without omalizumab.

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Molecular signatures order the potency of topically applied anti-inflammatory drugs in atopic dermatitis patients

Our novel intra-patient evaluation of topical formulations found pronounced differences in biomarker responses between steroids, pimecrolimus, and emollient. While clinical and mechanistic data were congruent, the tissue analyses provided higher differentiation between various products.

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Role of C/EBP homologous protein (CHOP) and Endoplasmic Reticulum in Asthma Exacerbation by Regulating the IL-4/STAT6/Tfec/IL-4Rα Positive Feedback Loop in M2 Macrophages

CHOP exacerbates allergic asthma by regulating the IL-4/STAT6/Tfec/IL-4Rα positive feedback loop essential for M2 programming in macrophages, which are positively correlated with disease severity in asthmatic patients.

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Persistent kallikrein5 activation induces atopic dermatitis-like skin architecture independent of PAR2 activity

Persistently increased serine protease kallikrein 5 modifies skin barrier proteins, upregulates AD-related cytokine expression and induces AD-like skin architecture. Inhibition of KLK5 may offer potential as a treatment strategy in AD.

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Microparticles in nasal lavage fluids in chronic rhinosinusitis; potential biomarkers for diagnosis of Aspirin Exacerbated Respiratory Disease

Microparticles are released into the nasal cavity from activated immune cells and injured structural cells in CRS and AERD. Assessment of microparticle levels in nasal lavage fluid may help distinguish the various phenotypes, especially AERD.

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KIF3A genetic variation is associated with pediatric asthma in the presence of eczema independent of allergic rhinitis

KIF3A SNPs identify a subset of asthmatic children with prior or current eczema independent of AR, and may be useful biomarkers of an eczema phenotype that progresses to asthma, independent of allergic sensitization.

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Asthma Remission: Predicting Future Airways Responsiveness using a miRNA Network

A panel of circulating microRNAs can be used to predict airway hyperresponsiveness remission in growing children with asthma as they transition into adolescence and adulthood.

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Seasonal Variability of Severe Asthma Exacerbations and Clinical Benefit from Lebrikizumab

Post-hoc analyses of two Phase III studies of lebrikizumab in moderate to severe asthma suggest that IL-13 inhibition is effective at preventing seasonal exacerbations in subjects with high blood eosinophil counts. Further work is required to understand and treat exacerbations that are independent of seasonal and Type 2 pathway factors.

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Editorial Board and Contents

Publication date: March 2017
Source:Trends in Immunology, Volume 38, Issue 3





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Radionuclide therapy of malignant bone lesions



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18F-FDG PET/CT in gastric MALT lymphoma: a bicentric experience

Abstract

Purpose

The role of 18F-FDG-PET/CT in evaluating gastric MALT lymphoma is still controversial. In the literature the detection rate of 18F-FDG-PET/CT in patients with gastric MALT lymphoma is variable, and the reason for this heterogeneity is not still clear. Our aim was to investigate the particular metabolic behavior of these lymphoma.

Materials and methods

Sixty-nine patients (26 female, 43 male) with histologically confirmed gastric MALT lymphoma who underwent a 18F-FDG-PET/CT for initial staging from two centers were included. The PET images were analyzed visually and semi-quantitatively by measuring the maximum standardized uptake value (SUVmax), lesion-to-liver SUVmax ratio, and lesion-to-blood pool SUVmax ratio and compared with Ann Arbor stage, epidemiological (age, sex), histological (presence of gastritis, ulcer, H. pylori infection, plasmacytic differentiation, Ki-67 index), and morphological (tumor size, superficial lesions or mass-forming) characteristics.

Results

Thirty-six patients (52 %) had positive PET/CT (average SUVmax was 9±6.7; lesion-to-liver SUVmax ratio 3.7±2.6, lesion-to-blood pool SUVmax ratio 4.8±3.3) at the corresponding gastric lesion; the remaining 33 were not 18F-FDG-avid. In the univariate analysis, 18F-FDG avidity was significantly associated with morphological features (mass forming p<0.001 and high maximum diameter p<0.001), Ann Arbor stage (p=0.010), and Ki67 index (p<0.001) and not correlated with age, sex, presence of gastritis, ulcer, Helicobacter pylori infection, and plasmacytic differentiation. In the multivariate analysis, the correlations with gross morphological appearance, Ann Arbor stage, and Ki-67 score were confirmed. SUVmax, lesion-to-liver SUVmax ratio, and lesion-to-blood pool SUVmax ratio correlated significantly only with Ki67 index (p=0.047; p=0.012; p=0.042).

Conclusions

18F-FDG avidity was noted in 52 % of gastric MALT lymphoma and this avidity is correlated with gross morphological characteristics, tumor stage, and Ki-67 index. SUVmax, lesion-to-liver SUVmax ratio, and lesion-to-blood pool SUVmax ratio are correlated only with Ki-67 index, and only lesion-to-liver SUVmax ratio was independently associated with Ki-67 score.



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Diffuse 18 F-FDG accumulation in the subarachnoid space detected by PET/CT in a patient with subarachnoid hemorrhage and hyperglycemia



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Targets and probes for non-invasive imaging of β-cells

Abstract

β-cells, located in the islets of the pancreas, are responsible for production and secretion of insulin and play a crucial role in blood sugar regulation. Pathologic β-cells often cause serious medical conditions affecting blood glucose level, which severely impact life quality and are life-threatening if untreated. With 347 million patients, diabetes is one of the most prevalent diseases, and will continue to be one of the largest socioeconomic challenges in the future. The diagnosis still relies mainly on indirect methods like blood sugar measurements. A non-invasive diagnostic imaging modality would allow direct evaluation of β-cell mass and would be a huge step towards personalized medicine. Hyperinsulinism is another serious condition caused by β-cells that excessively secrete insulin, like for instance β-cell hyperplasia and insulinomas. Treatment options with drugs are normally not curative, whereas curative procedures usually consist of the resection of affected regions for which, however, an exact localization of the foci is necessary. In this review, we describe potential tracers under development for targeting β-cells with focus on radiotracers for PET and SPECT imaging, which allow the non-invasive visualization of β-cells. We discuss either the advantages or limitations for the various tracers and modalities. This article concludes with an outlook on future developments and discuss the potential of new imaging probes including dual probes that utilize functionalities for both a radioactive and optical moiety as well as for theranostic applications.



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Erratum to: A rare case of rectal carcinoma and prostate carcinoma with coexistent Paget’s disease mimicking bone metastases in both 18F-FDG and 68Ga PSMA PET/CT



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The intensity of 18FDG uptake does not predict tumor growth in patients with metastatic differentiated thyroid cancer

Abstract

Purpose

In patients with metastatic differentiated thyroid carcinoma (DTC), fluorodeoxyglucose (FDG) uptake as well as age, tumor size and radioactive iodine (RAI) uptake are prognostic factors for survival. High FDG uptake is a poor prognostic factor and lesions with high FDG uptake are often considered aggressive, but the predictive value of FDG uptake for morphological progression is unknown. The principal aim of this retrospective single center study was to determine whether the intensity of FDG uptake was correlated on a per lesion analysis with tumor growth rate (TGR) expressed as the percentage of increase in tumor size during 1 year (1-year TGR).

Methods

Fifty five patients with DTC were included between July 2012 and May 2014 with the following criteria: (i) at least one distant metastasis measuring ≥ 1 cm in diameter on CT scan (ii) evaluation by FDG-positron emission tomography/computed tomography (PET/CT) performed at our center (iii) at least one CT or another FDG-PET/CT performed 3 to 12 months after the reference FDG-PET/CT in the absence of systemic or local treatment between the two imaging procedures.

Results

One hundred and fifty-six metastatic lesions located in lungs (63), neck lymph nodes (28), chest lymph nodes (42), bone (11), liver (2) and other sites (12) were studied. The median size was 16 mm, median SUVmax/lesion: 8.7; median metabolic tumor volume/lesion (Metab.TV/lesion): 3.7 cm3. The median 1-year TGR was 40.68 %. SUVmax and Metab.TV/lesion were not correlated to their 1-year TGR (p = 0.38 and p = 0.74 respectively). Among single patients with multiple lesions, the lesions with the highest SUVmax/lesion or the highest Metab.TV/lesion did not disclose the higher 1-year TGR.

Conclusion

The intensity of FDG uptake on a per lesion analysis is not correlated to its 1-year TGR and cannot be used as a surrogate marker of tumour progression.



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THIEME Atlas of Anatomy – Internal Organs , 2nd Edition. Michael Schuenke, Erik Schulte, Udo Schumacher (Editors), Wayne A. Cass (Consulting Editor), Markus Voll, Karl Wesker (Illustrations)



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Phase I/II trials of 186 Re-HEDP in metastatic castration-resistant prostate cancer: post-hoc analysis of the impact of administered activity and dosimetry on survival

Abstract

Purpose

To investigate the role of patient-specific dosimetry as a predictive marker of survival and as a potential tool for individualised molecular radiotherapy treatment planning of bone metastases from castration-resistant prostate cancer, and to assess whether higher administered levels of activity are associated with a survival benefit.

Methods

Clinical data from 57 patients who received 2.5–5.1 GBq of 186Re-HEDP as part of NIH-funded phase I/II clinical trials were analysed. Whole-body and SPECT-based absorbed doses to the whole body and bone lesions were calculated for 22 patients receiving 5 GBq. The patient mean absorbed dose was defined as the mean of all bone lesion-absorbed doses in any given patient. Kaplan–Meier curves, log-rank tests, Cox’s proportional hazards model and Pearson’s correlation coefficients were used for overall survival (OS) and correlation analyses.

Results

A statistically significantly longer OS was associated with administered activities above 3.5 GBq in the 57 patients (20.1 vs 7.1 months, hazard ratio: 0.39, 95 % CI: 0.10–0.58, P = 0.002). A total of 379 bone lesions were identified in 22 patients. The mean of the patient mean absorbed dose was 19 (±6) Gy and the mean of the whole-body absorbed dose was 0.33 (±0.11) Gy for the 22 patients. The patient mean absorbed dose (r = 0.65, P = 0.001) and the whole-body absorbed dose (r = 0.63, P = 0.002) showed a positive correlation with disease volume. Significant differences in OS were observed for the univariate group analyses according to disease volume as measured from SPECT imaging of 186Re-HEDP (P = 0.03) and patient mean absorbed dose (P = 0.01), whilst only the disease volume remained significant in a multivariable analysis (P = 0.004).

Conclusion

This study demonstrated that higher administered activities led to prolonged survival and that for a fixed administered activity, the whole-body and patient mean absorbed doses correlated with the extent of disease, which, in turn, correlated with survival. This study shows the importance of patient stratification to establish absorbed dose–response correlations and indicates the potential to individualise treatment of bone metastases with radiopharmaceuticals according to patient-specific imaging and dosimetry.



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Stefano Fanti and Egesta Lopci (Editors): Diagnostic nuclear medicine and radionuclide therapy



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Michael Schuenke, Erik Schulte, Udo Schumacher (Editors): Atlas of anatomy: head, neck, and neuroanatomy



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Detection rate of PET/CT in patients with biochemical relapse of prostate cancer using [ 68 Ga]PSMA I&T and comparison with published data of [ 68 Ga]PSMA HBED-CC

Abstract

Purpose

To determine the detection rate of PET/CT in biochemical relapse of prostate cancer using [68Ga]PSMA I&T and to compare it with published detection rates of [68Ga]PSMA HBED-CC.

Methods

We performed a retrospective analysis in 83 consecutive patients with documented biochemical relapse after prostatectomy. All patients underwent whole body [68Ga]PSMA I&T PET/CT. PET/CT images were evaluated for presence of local recurrence, lymph node metastases, and distant metastases. Proportions of positive PET/CT results were calculated for six subgroups with increasing prostate specific antigen (PSA) levels (<0.5 ng/mL, 0.5 to <1.0 ng/mL, 1.0 to <2.0 ng/mL, 2.0 to <5.0 ng/mL, 5.0 to <10.0, ≥10.0 ng/mL). Detection rates of [68Ga]PSMA I&T were statistically compared with published detection rates of [68Ga]PSMA HBED-CC using exact Fisher’s test.

Results

Median PSA was 0.81 (range: 0.01 – 128) ng/mL. In 58/83 patients (70 %) at least one [68Ga]PSMA I&T positive lesion was detected. Local recurrent cancer was present in 18 patients (22 %), lymph node metastases in 29 patients (35 %), and distant metastases in 15 patients (18 %). The tumor detection rate was positively correlated with PSA levels, resulting in detection rates of 52 % (<0.5 ng/mL), 55 % (0.5 to <1.0 ng/mL), 70 % (1.0 to <2.0 ng/mL), 93 % (2.0 to <5.0 ng/mL), 100 % (5.0 to <10.0 ng/mL), and 100 % (≥10.0 ng/mL). There was no significant difference between the detection rate of [68Ga]PSMA I&T and published detection rates of [68Ga]PSMA HBED-CC (all p>0.05).

Conclusions

[68Ga]PSMA I&T PET/CT has high detection rates of recurrent prostate cancer that are comparable to [68Ga]PSMA HBED-CC.



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Contribution of SPECT/CT for sentinel node localization in patients with ipsilateral breast cancer relapse

Abstract

Background

In recent years repeat sentinel node (SN) biopsy has been proven to be feasible in local breast cancer recurrence (LBCR). However, in these patients SNs outside the ipsilateral axilla are frequently observed. This study evaluates the contribution of SPECT/CT for SN localization and surgical adjustment in LBCR patients.

Methods

SN biopsy was performed in 122 LBCR patients (median age 60.5 years, range 24–87), enrolled from August 2006 to July 2015. Median disease-free time lapse was 109.5 months (range 9–365). Axillary lymph node dissection (ALND) had previously been performed in 55 patients, SN biopsy in 44, both techniques in 13 and fine-needle aspiration in 10. Primary breast cancer treatment included radiotherapy in 104 patients (85.3 %) and chemotherapy in 40 (32.8 %). Preoperative lymphatic mapping, using planar scintigraphy (PS) and SPECT/CT included report of SN location according to lymph node territory. In case of a territorial PS-SPECT/CT mismatch, surgery was adjusted according to SPECT/CT findings.

Results

SPECT/CT SN visualization rate was higher than PS (53.3 % vs. 43.4 %, p n.s.) with, in total, 19 additional SN (118 vs. 99, p n.s.). PS-SPECT/CT territory mismatch, found in 60 % (39/65) of patients with SN visualization, led to surgical adjustment in 21.3 % (26/122) of patients. The SN procedure was finally performed in 104 patients resulting in a 65.7 % surgical retrieval rate with a total of 132 removed SNs (1.86/patient). SN metastases were found in 17/71 patients (23.9 %), in 16 of them (94 %) in ipsilateral basins outside the axilla or in the contralateral axilla.

Conclusion

Using SPECT/CT there is a trend to visualize more SNs in LBCR, providing at the same time important anatomical information to adjust intraoperative SN procedures. The addition of SPECT/CT to the standard imaging protocol may lead to better staging mainly in patients presenting drainage outside the ipsilateral axilla.



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Efficacy of qualitative response assessment interpretation criteria at 18F-FDG PET-CT for predicting outcome in locally advanced cervical carcinoma treated with chemoradiotherapy

Abstract

Objectives

To evaluate the utility of a standardized qualitative scoring system for treatment response assessment at 18F-FDG PET-CT in patients undergoing chemoradiotherapy for locally advanced cervical carcinoma and correlate this with subsequent patient outcome.

Methods

Ninety-six consecutive patients with locally advanced cervical carcinoma treated with radical chemoradiotherapy (CRT) in a single centre between 2011 and 2014 underwent 18F-FDG PET-CT approximately 3 months post-treatment. Tumour metabolic response was assessed qualitatively using a 5-point scale ranging from background level activity only through to progressive metabolic disease. Clinical and radiological (MRI pelvis) follow-up was performed in all patients. Progression-free (PFS) and overall survival (OS) was calculated using the Kaplan-Meier method (Mantel-Cox log-rank) and correlated with qualitative score using Chi-squared test.

Results

Forty patients (41.7 %) demonstrated complete metabolic response (CMR) on post-treatment PET-CT (Score 1/2) with 38 patients (95.0 %) remaining disease free after a minimum follow-up period of 18 months. Twenty-four patients (25.0 %) had indeterminate residual uptake (ID, Score 3) at primary or nodal sites after treatment, of these eight patients (33.3 %) relapsed on follow-up, including all patients with residual nodal uptake (n = 4Eleven11 of 17 patients (64.7 %) with significant residual uptake (partial metabolic response, PMR, Score 4) subsequently relapsed. In 15 patients (15.6 %) PET-CT demonstrated progressive disease (PD, Score 5) following treatment. Kaplan-Meier analysis showed a highly statistically significant difference in PFS and OS between patients with CMR, indeterminate uptake, PMR and PD (Log-rank, P < 0.0001). Chi-squared test demonstrated a highly statistically significant association between increasing qualitative score and risk of recurrence or death (P < 0.001).

Conclusion

Use of a 5-point qualitative scoring system to assess metabolic response to CRT in locally advanced cervical carcinoma predicts survival outcome and this prognostic information may help guide further patient management.



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The reconstruction algorithm used for [ 68 Ga]PSMA-HBED-CC PET/CT reconstruction significantly influences the number of detected lymph node metastases and coeliac ganglia

Abstract

Purpose

To investigate whether the numbers of lymph node metastases and coeliac ganglia delineated on [68Ga]PSMA-HBED-CC PET/CT scans differ among datasets generated using different reconstruction algorithms.

Methods

Data were constructed using the BLOB-OS-TF, BLOB-OS and 3D-RAMLA algorithms. All reconstructions were assessed by two nuclear medicine physicians for the number of pelvic/paraaortal lymph node metastases as well the number of coeliac ganglia. Standardized uptake values (SUV) were also calculated in different regions.

Results

At least one [68Ga]PSMA-HBED-CC PET/CT-positive pelvic or paraaortal lymph node metastasis was found in 49 and 35 patients using the BLOB-OS-TF algorithm, in 42 and 33 patients using the BLOB-OS algorithm, and in 41 and 31 patients using the 3D-RAMLA algorithm, respectively, and a positive ganglion was found in 92, 59 and 24 of 100 patients using the three algorithms, respectively. Quantitatively, the SUVmean and SUVmax were significantly higher with the BLOB-OS algorithm than with either the BLOB-OS-TF or the 3D-RAMLA algorithm in all measured regions (p < 0.001 for all comparisons). The differences between the SUVs with the BLOB-OS-TF- and 3D-RAMLA algorithms were not significant in the aorta (SUVmean, p = 0.93; SUVmax, p = 0.97) but were significant in all other regions (p < 0.001 in all cases). The SUVmean ganglion/gluteus ratio was significantly higher with the BLOB-OS-TF algorithm than with either the BLOB-OS or the 3D-RAMLA algorithm and was significantly higher with the BLOB-OS than with the 3D-RAMLA algorithm (p < 0.001 in all cases).

Conclusion

The results of [68Ga]PSMA-HBED-CC PET/CT are affected by the reconstruction algorithm used. The highest number of lesions and physiological structures will be visualized using a modern algorithm employing time-of-flight information.



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68 Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients

Abstract

Background

To report on imaging findings using 68Ga-PSMA-HBED-CC PET in a series of 19 breast carcinoma patients.

Methods

68Ga-PSMA-HBED-CC PET imaging results obtained were compared to routinely performed staging examinations and analyzed as to lesion location and progesterone receptor status.

Results

Out of 81 tumor lesions identified, 84% were identified on 68Ga-PSMA-HBED-CC PET. 68Ga-PSMA-HBED-CC SUVmean values of distant metastases proved significantly higher (mean, 6.86, SD, 5.68) when compared to those of primary or local recurrences (mean, 2.45, SD, 2.55, p = 0.04) or involved lymph nodes (mean, 3.18, SD, 1.79, p = 0.011). SUVmean values of progesterone receptor-positive lesions proved not significantly different from progesterone receptor-negative lesions. SUV values derived from FDG PET/CT, available in seven patients, and 68Ga-PSMA-HBED-CC PET/CT imaging proved weakly correlated (r = 0.407, p = 0.015).

Conclusions

68Ga-PSMA-HBED-CC PET/CT imaging in breast carcinoma confirms the reported considerable variation of PSMA expression on human solid tumors using immunohistochemistry.



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Synthesis and pre-clinical evaluation of a new class of high-affinity 18 F-labeled PSMA ligands for detection of prostate cancer by PET imaging

Abstract

Purpose

Current clinical imaging of PSMA-positive prostate cancer by positron emission tomography (PET) mainly features 68Ga-labeled tracers, notably [68Ga]Ga-PSMA-HBED-CC. The longer half-life of fluorine-18 offers significant advantages over Ga-68, clinically and logistically. We aimed to develop high-affinity PSMA inhibitors labeled with fluorine-18 as alternative tracers for prostate cancer.

Methods

Six triazolylphenyl ureas and their alkyne precursors were synthesized from the Glu-urea-Lys PSMA binding moiety. PSMA affinity was determined in a competitive binding assay using LNCaP cells. The [18F]triazoles were isolated following a Cu(I)-catalyzed click reaction between the alkynes and [18F]fluoroethylazide. The 18F-labeled compounds were evaluated in nude mice bearing LNCaP tumors and compared to [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL. Biodistribution studies of the two tracers with the highest imaged-derived tumor uptake and highest PSMA affinity were undertaken at 1 h, 2 h and 4 h post-injection (p.i.), and co-administration of PMPA was used to determine whether uptake was PSMA-specific.

Results

F-18-labeled triazolylphenyl ureas were prepared with a decay-corrected RCY of 20–40 %, >98 % radiochemical and chemical purity, and specific activity of up to 391 GBq/μmol. PSMA binding (IC50) ranged from 3–36 nM. The position of the triazole influenced tumor uptake (3 > 4 > 2), and direct conjugation of the triazole with the phenylurea moiety was preferred to insertion of a spacer group. Image-derived tumor uptake ranged from 6–14 %ID/g at 2 h p.i., the time of maximum tumor uptake; uptake of [68Ga]Ga-PSMA-HBED-CC and [18F]DCFPyL was 5–6 %ID/g at 1–3 h p.i., the time of maximum tumor uptake. Biodistribution studies of the two most promising compounds gave maximum tumor uptakes of 10.9 ± 1.0 % and 14.3 ± 2.5 %ID/g, respectively, as compared to 6.27 ± 1.44 %ID/g for [68Ga]Ga-PSMA-HBED-CC.

Conclusions

Six [18F]triazolylphenyl ureas were prepared in good radiochemical yield. Compounds showed PSMA-specific uptake in LNCaP tumors as high as 14 % ID/g, more than a 2-fold increase over [68Ga]Ga-PSMA-HBED-CC. The facile and high-yielding radiosynthesis of these 18F-labeled triazoles as well as their promising in vitro and in vivo characteristics make them worthy of clinical development for PET imaging of prostate cancer.



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Reply by L. Maffioli



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F-18 labelled PSMA-1007: biodistribution, radiation dosimetry and histopathological validation of tumor lesions in prostate cancer patients

Abstract

Purpose

The prostate-specific membrane antigen (PSMA) targeted positron-emitting-tomography (PET) tracer 68Ga-PSMA-11 shows great promise in the detection of prostate cancer. However, 68Ga has several shortcomings as a radiolabel including short half-life and non-ideal energies, and this has motivated consideration of 18F-labelled analogs. 18F-PSMA-1007 was selected among several 18F-PSMA-ligand candidate compounds because it demonstrated high labelling yields, outstanding tumor uptake and fast, non-urinary background clearance. Here, we describe the properties of 18F-PSMA-1007 in human volunteers and patients.

Methods

Radiation dosimetry of 18F-PSMA-1007 was determined in three healthy volunteers who underwent whole-body PET-scans and concomitant blood and urine sampling. Following this, ten patients with high-risk prostate cancer underwent 18F-PSMA-1007 PET/CT (1 h and 3 h p.i.) and normal organ biodistribution and tumor uptakes were examined. Eight patients underwent prostatectomy with extended pelvic lymphadenectomy. Uptake in intra-prostatic lesions and lymph node metastases were correlated with final histopathology, including PSMA immunostaining.

Results

With an effective dose of approximately 4.4–5.5 mSv per 200–250 MBq examination, 18F-PSMA-1007 behaves similar to other PSMA-PET agents as well as to other 18F-labelled PET-tracers. In comparison to other PSMA-targeting PET-tracers, 18F-PSMA-1007 has reduced urinary clearance enabling excellent assessment of the prostate. Similar to 18F-DCFPyL and with slightly slower clearance kinetics than PSMA-11, favorable tumor-to-background ratios are observed 2–3 h after injection. In eight patients, diagnostic findings were successfully validated by histopathology. 18F-PSMA-1007 PET/CT detected 18 of 19 lymph node metastases in the pelvis, including nodes as small as 1 mm in diameter.

Conclusion

18F-PSMA-1007 performs at least comparably to 68Ga-PSMA-11, but its longer half-life combined with its superior energy characteristics and non-urinary excretion overcomes some practical limitations of 68Ga-labelled PSMA-targeted tracers.



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