Immune modulation in advanced radiotherapies: Targeting out-of-field effects

By virtue of being a localized treatment modality, radiotherapy is unable to deliver a tumoricidal radiation dose to tissues outside of the irradiated field. Nevertheless, ionizing radiation may result in radiation damage mediated by a bystander like effect away from the irradiated field, but this response is likely to be modest when radiotherapy is the sole treatment modality. Over the last decade there has been a re-emergence of immune modulating therapies as anti-cancer treatment modalities. Clinical trials on vaccines have on the whole been largely disappointing, but greater response rates have been observed from the immune checkpoint modulators. A clinical benefit of using such agents has been shown in disease sites such as melanoma and non-small cell lung cancer. There is growing pre-clinical data and a number of case reports which suggest the presence of abscopal effects when radiotherapy is co-administered with immune checkpoint inhibitors, suggesting that this combination may lead to an enhanced tumour response outside of the primary treatment field. In this review, the mechanisms of such an enhanced out-of-field tumour response, the potential clinical utilities, the optimal radiotherapy delivery and considerations for clinical follow-up following treatment are discussed.

Epigenetic Changes in Endothelial Progenitors as a Possible Cellular Basis for Glycemic Memory in Diabetic Vascular Complications

The vascular complications of diabetes significantly impact the quality of life and mortality in diabetic patients. Extensive evidence from various human clinical trials has clearly established that a period of poor glycemic control early in the disease process carries negative consequences, such as an increase in the development and progression of vascular complications that becomes evident many years later. Importantly, intensive glycemic control established later in the disease process cannot reverse or slow down the onset or progression of diabetic vasculopathy. This has been named the glycemic memory phenomenon. Scientists have successfully modelled glycemic memory using various in vitro and in vivo systems. This review emphasizes that oxidative stress and accumulation of advanced glycation end products are key factors driving glycemic memory in endothelial cells. Furthermore, various epigenetic marks have been proposed to closely associate with vascular glycemic memory. In addition, we comment on the importance of endothelial progenitors and their role as endogenous vasoreparative cells that are negatively impacted by the diabetic milieu and may constitute a "carrier" of glycemic memory. Considering the potential of endothelial progenitor-based cytotherapies, future studies on their glycemic memory are warranted to develop epigenetics-based therapeutics targeting diabetic vascular complications.

Rationale and Means to Target Pro-Inflammatory Interleukin-8 (CXCL8) Signaling in Cancer

It is well established that chronic inflammation underpins the development of a number of human cancers, with pro-inflammatory signaling within the tumor microenvironment contributing to tumor progression and metastasis. CXCL8 is an ELR+ pro-inflammatory CXC-chemokine which mediates its effects via signaling through two G protein-coupled receptors, CXCR1 and CXCR2. Elevated CXCL8-CXCR1/2 signaling within the tumor microenvironment of numerous cancers is known to enhance tumor progression via activation of signaling pathways promoting proliferation, angiogenesis, migration, invasion and cell survival. This review provides an overview of established roles of CXCL8-CXCR1/2 signaling in cancer and subsequently, discusses the possible strategies of targeting CXCL8-CXCR1/2 signaling in cancer, covering indirect strategies (e.g., anti-inflammatories, NFκB inhibitors) and direct CXCL8 or CXCR1/2 inhibition (e.g., neutralizing antibodies, small molecule receptor antagonists, pepducin inhibitors and siRNA strategies). Reports of pre-clinical cancer studies and clinical trials using CXCL8-CXCR1/2-targeting strategies for the treatment of inflammatory diseases will be discussed. The future translational opportunities for use of such agents in oncology will be discussed, with emphasis on exploitation in stratified populations.

Progress on core outcomes sets for critical care research

Purpose of review: Appropriate selection and definition of outcome measures are essential for clinical trials to be maximally informative. Core outcome sets (an agreed, standardized collection of outcomes measured and reported in all trials for a specific clinical area) were developed due to established inconsistencies in trial outcome selection. This review discusses the rationale for, and methods of, core outcome set development, as well as current initiatives in critical care.

Recent findings: Recent systematic reviews of reported outcomes and measurement instruments relevant to the critically ill highlight inconsistencies in outcome selection, definition, and measurement, thus establishing the need for core outcome sets. Current critical care initiatives include development of core outcome sets for trials aimed at reducing mechanical ventilation duration; rehabilitation following critical illness; long-term outcomes in acute respiratory failure; and epidemic and pandemic studies of severe acute respiratory infection.

Summary: Development and utilization of core outcome sets for studies relevant to the critically ill is in its infancy compared to other specialties. Notwithstanding, core outcome set development frameworks and guidelines are available, several sets are in various stages of development, and there is strong support from international investigator-led collaborations including the International Forum for Acute Care Trialists.

Topical antihistamines and mast cell stabilisers for treating seasonal and perennial allergic conjunctivitis

BACKGROUND: Seasonal/perennial allergic conjunctivitis is the most common allergic conjunctivitis, usually with acute manifestations when a person is exposed to allergens and with typical signs and symptoms including itching, redness, and tearing. The clinical signs and symptoms of allergic conjunctivitis are mediated by the release of histamine by mast cells. Histamine antagonists (also called antihistamines) inhibit the action of histamine by blocking histamine H1 receptors, antagonising the vasoconstrictor, and to a lesser extent, the vasodilator effects of histamine. Mast cell stabilisers inhibit degranulation and consequently the release of histamine by interrupting the normal chain of intracellular signals. Topical treatments include eye drops with antihistamines, mast cell stabilisers, non-steroidal anti-inflammatory drugs, combinations of the previous treatments, and corticosteroids. Standard treatment is based on topical antihistamines alone or topical mast cell stabilisers alone or a combination of treatments. There is clinical uncertainty about the relative efficacy and safety of topical treatment.

OBJECTIVES: The objective of this review was to assess the effects of topical antihistamines and mast cell stabilisers, alone or in combination, for use in treating seasonal and perennial allergic conjunctivitis.

SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2014, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2014), EMBASE (January 1980 to July 2014), the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 17 July 2014. We also searched the reference lists of review articles and relevant trial reports for details of further relevant publications.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing topical antihistamine and mast cell stabilisers, alone or in combination, with placebo, no treatment or to any other antihistamine or mast cell stabiliser, or both, that examined people with seasonal or perennial allergic conjunctivitis, or both. The primary outcome was any participant-reported evaluation (by questionnaire) of severity of four main ocular symptoms: itching, irritation, watering eye (tearing), and photophobia (dislike of light), both separately and, if possible, by an overall symptom score. We considered any follow-up time between one week and one year.

DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed risk of bias. Disagreements were resolved by discussion among review authors and the involvement of a third review author. We followed standard methodological approaches used by Cochrane.

MAIN RESULTS: We identified 30 trials with a total of 4344 participants randomised, with 17 different drugs or treatment comparisons. The following antihistamines and mast cell stabilisers were evaluated in at least one RCT: nedocromil sodium or sodium cromoglycate, olopatadine, ketotifen, azelastine, emedastine, levocabastine (or levocabastine), mequitazine, bepotastine besilate, combination of antazoline and tetryzoline, combination of levocabastine and pemirolast potassium. The most common comparison was azelastine versus placebo (nine studies).We observed a large variability in reporting outcomes. The quality of the studies and reporting was variable, but overall the risk of bias was low. Trials evaluated only short-term effects, with a range of treatment of one to eight weeks. Meta-analysis was only possible in one comparison (olopatadine versus ketotifen). There was some evidence to support that topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo. There were no reported serious adverse events related to the use of topical antihistamine and mast cell stabilisers treatment.

AUTHORS' CONCLUSIONS: It seems that all reported topical antihistamines and mast cell stabilisers reduce symptoms and signs of seasonal allergic conjunctivitis when compared with placebo in the short term. However, there is no long-term data on their efficacy. Direct comparisons of different antihistamines and mast cell stabilisers need to be interpreted with caution. Overall, topical antihistamines and mast cell stabilisers appear to be safe and well tolerated. We observed a large variability in outcomes reported. Poor quality of reporting challenged the synthesis of evidence.

Smac-derived Aza-peptide As an Aminopeptidase-resistant XIAP BIR3 Antagonist

The peptidic nature of anti-IAPs N-terminus Smac-derived peptides precludes their utilization as potential therapeutic anticancer agents. Recent advances in the development of novel Smac-derived peptidomimetics and non-peptidic molecules with improved anti-IAPs activity and resistance to proteolytic cleavage have been reported and led to a number of candidates that are currently in clinical trials including LCL-161, SM-406/AT-406, GDC-0512/GDC-0917, and birinapant. As an attempt to improve the proteolytic stability of Smac peptides, we developed the Aza-peptide AzaAla-Val-Pro-Phe-Tyr-NH2 (2). Unlike unmodified peptide Ala-Val-Pro-Phe-Tyr-NH2 (1), analogue (2) exhibited resistance towards proteolytic cleavage by two aminopeptidases; LAP and DPP-IV, while retaining its IAP inhibitory activity. This was due to the altered planar geometry of the P1 residue side chain. Our findings showed that using aza-isosteres of bioactive peptide sequences imbue the residue with imperviousness to proteolysis; underscoring a potential approach for developing a new generation of Smac-derived Aza-peptidomimetics.

Multidimensional rehabilitation programmes for adult cancer survivors

Background: Multidimensional rehabilitation programmes (MDRPs) have developed in response to the growing number of people living with and surviving cancer. MDRPs comprise a physical component and a psychosocial component. Studies of the effectiveness of these programmes have not been reviewed and synthesised.

Objectives: To conduct a systematic review of studies examining the effectiveness of MDRPs in terms of maintaining or improving the physical and psychosocial well-being of adult cancer survivors.

Search methods: We conducted electronic searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, CINAHL and PsychINFO up to February 2012.

Selection criteria: Selection criteria focused on randomised controlled trials (RCTs) of multidimensional interventions for adult cancer survivors. Interventions had to include a physical component and a psychosocial component and to have been carried out on two or more occasions following completion of primary cancer treatment. Outcomes had to be assessed using validated measures of physical health and psychosocial well-being. Non-English language papers were included.

Data collection and analysis: Pairs of review authors independently selected trials, rated their methodological quality and extracted relevant data. Although meta-analyses of primary and secondary endpoints were planned there was a high level of study heterogeneity and only one common outcome measure (SF-36) could be statistically synthesised. In addition, we conducted a narrative analysis of interventions, particularly in terms of inspecting and identifying intervention components, grouping or categorising interventions and examining potential common links and outcomes.

Main results: Twelve RCTs (comprising 1669 participants) met the eligibility criteria. We judged five studies to have a moderate risk of bias and assessed the remaining seven as having a high risk of bias. It was possible to include SF-36 physical health component scores from five studies in a meta-analysis. Participating in a MDRP was associated with an increase in SF-36 physical health component scores (mean difference (MD) 2.22, 95% confidence interval (CI) 0.12 to 4.31, P = 0.04). The findings from the narrative analysis suggested that MDRPs with a single domain or outcome focus appeared to be more successful than programmes with multiple aims. In addition, programmes that comprised participants with different types of cancer compared to cancer site-specific programmes were more likely to show positive improvements in physical outcomes. The most effective mode of service delivery appeared to be face-to-face contact supplemented with at least one follow-up telephone call. There was no evidence to indicate that MDRPs which lasted longer than six months improved outcomes beyond the level attained at six months. In addition, there was no evidence to suggest that services were more effective if they were delivered by a particular type of health professional.

Authors' conclusions: There is some evidence to support the effectiveness of brief, focused MDRPs for cancer survivors. Rigorous and methodologically sound clinical trials that include an economic analysis are required.

Infection control strategies for preventing the transmission of meticillin-resistant Staphylococcus aureus (MRSA) in nursing homes for older people (Review)

Background: Nursing homes for older people provide an environment likely to promote the acquisition and spread of meticillin-resistant Staphylococcus aureus (MRSA), putting residents at increased risk of colonisation and infection. It is recognised that infection prevention and control strategies are important in preventing and controlling MRSA transmission.

Objectives: To determine the effects of infection prevention and control strategies for preventing the transmission of MRSA in nursing homes for older people.

Search methods: In August 2013, for this third update, we searched the Cochrane Wounds Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library), Database of Abstracts of Reviews of Effects (DARE, The Cochrane Library), Ovid MEDLINE, OVID MEDLINE (In-process and Other Non-Indexed Citations), Ovid EMBASE, EBSCO CINAHL, Web of Science and the Health Technology Assessment (HTA) website. Research in progress was sought through Current Clinical Trials, Gateway to Reseach, and HSRProj (Health Services Research Projects in Progress).

Selection criteria: All randomised and controlled clinical trials, controlled before and after studies and interrupted time series studies of infection prevention and control interventions in nursing homes for older people were eligible for inclusion.

Data collection and analysis: Two review authors independently reviewed the results of the searches. Another review author appraised identified papers and undertook data extraction which was checked by a second review author.

Main results: For this third update only one study was identified, therefore it was not possible to undertake a meta-analysis. A cluster randomised controlled trial in 32 nursing homes evaluated the effect of an infection control education and training programme on MRSA prevalence. The primary outcome was MRSA prevalence in residents and staff, and a change in infection control audit scores which measured adherence to infection control standards. At the end of the 12 month study, there was no change in MRSA prevalence between intervention and control sites, while mean infection control audit scores were significantly higher in the intervention homes compared with control homes.

Authors' conclusions: There is a lack of research evaluating the effects on MRSA transmission of infection prevention and control strategies in nursing homes. Rigorous studies should be conducted in nursing homes, involving residents and staff to test interventions that have been specifically designed for this unique environment.

Genomics and the impact of new technologies on the management of colorectal cancer

High-throughput genomic technologies have the potential to have a major impact on preclinical and clinical drug development and the selection and stratification of patients in clinical trials. These technologies, which are at varying stages of commercialization, include array-based comparative genomic hybridization, single-nucleotide polymorphism arrays, and (the most mature example) expression-based arrays. One of the rate-limiting steps in the routine clinical application of expression array-based technology is the need for suitable clinical samples. One of the major challenges moving forward, therefore, relates to the ability to use formalin-fixed, paraffin-embedded--derived tissue in expression profiling-based approaches.

Pharmacokinetics of melatonin in preterm infants

Aims: Preterm infants are deprived of the normal intra-uterine exposure to maternal melatonin and may benefit from replacement therapy. We conducted a pharmacokinetic study to guide potential therapeutic trials. Methods: Melatonin was administered to 18 preterm infants in doses ranging from 0.04-0.6μgkg^-1 over 0.5-6h. Pharmacokinetic profiles were analyzed individually and by population methods. Results: Baseline melatonin was largely undetectable. Infants receiving melatonin at 0.1μgkg^-1h^-1 for 2h showed a median half-life of 15.82h and median maximum plasma concentration of 203.3pgml^-1. On population pharmacokinetics, clearance was 0.045lh^-1, volume of distribution 1.098l and elimination half-life 16.91h with gender (P = 0.047) and race (P < 0.0001) as significant covariates. Conclusions: A 2h infusion of 0.1μgkg^-1h^-1 increased blood melatonin from undetectable to approximately peak adult concentrations. Slow clearance makes replacement of a typical maternal circadian rhythm problematic. The pharmacokinetic profile of melatonin in preterm infants differs from that of adults so dosage of melatonin for preterm infants cannot be extrapolated from adult studies. Data from this study can be used to guide therapeutic clinical trials of melatonin in preterm infants. © 2013 The British Pharmacological Society.

Proteomics and in silico approaches to extend understanding of the glutathione transferase superfamily of the tropical liver fluke Fasciola gigantica

Fasciolosis is an important foodborne, zoonotic disease of livestock and humans, with global annual health and economic losses estimated at several billion US$. Fasciola hepatica is the major species in temperate regions, while F. gigantica dominates in the tropics. In the absence of commercially available vaccines to control fasciolosis, increasing reports of resistance to current chemotherapeutic strategies and the spread of fasciolosis into new areas, new functional genomics approaches are being used to identify potential new drug targets and vaccine candidates. The glutathione transferase (GST) superfamily is both a candidate drug and vaccine target. This study reports the identification of a putatively novel Sigma class GST, present in a water-soluble cytosol extract from the tropical liver fluke F. gigantica. The GST was cloned and expressed as an enzymically active recombinant protein. This GST shares a greater identity with the human schistosomiasis GST vaccine currently at Phase II clinical trials than previously discovered F. gigantica GSTs, stimulating interest in its immuno-protective properties. In addition, in silico analysis of the GST superfamily of both F. gigantica and F. hepatica has revealed an additional Mu class GST, Omega class GSTs, and for the first time, a Zeta class member.

A systematic review and meta-analysis of the survival of non-feldspathic porcelain veneers over 5 and 10 years

PURPOSE: This systematic review aimed to report and explore the survival of dental veneers constructed from non-feldspathic porcelain over 5 and 10 years.

MATERIALS AND METHODS: A total of 4,294 articles were identified through a systematic search involving all databases in the Cochrane Library, MEDLINE (OVID), EMBASE, Web of Knowledge, specific journals (hand-search), conference proceedings, clinical trials registers, and collegiate contacts. Articles, abstracts, and gray literature were sought by two independent researchers. There were no language limitations. One hundred sixteen studies were identified for full-text assessment, with 10 included in the analysis (5 qualitative, 5 quantitative). Study characteristics and survival (Kaplan-Meier estimated cumulative survival and 95% confidence interval [CI]) were extracted or recalculated. A failed veneer was one which required an intervention that disrupted the original marginal integrity, had been partially or completely lost, or had lost retention more than twice. A meta-analysis and sensitivity analysis of Empress veneers was completed, with an assessment of statistical heterogeneity and publication bias. Clinical heterogeneity was explored for results of all veneering materials from included studies.

RESULTS: Within the 10 studies, veneers were fabricated with IPS Empress, IPS Empress 2, Cerinate, and Cerec computer-aided design/computer-assisted manufacture (CAD/CAM) materials VITA Mark I, VITA Mark II, Ivoclar ProCad. The meta-analysis showed the pooled estimate for Empress veneers to be 92.4% (95% CI: 89.8% to 95.0%) for 5-year survival and 66% to 94% (95% CI: 55% to 99%) for 10 years. Data regarding other non-feldspathic porcelain materials were lacking, with only a single study each reporting outcomes for Empress 2, Cerinate, and various Cerec porcelains over 5 years. The sensitivity analysis showed data from one study had an influencing and stabilizing effect on the 5-year pooled estimate.

CONCLUSION: The long-term outcome (> 5 years) of non-feldspathic porcelain veneers is sparsely reported in the literature. This systematic review indicates that the 5-year cumulative estimated survival for etchable non-feldspathic porcelain veneers is over 90%. Outcomes may prove clinically acceptable with time, but evidence remains lacking and the use of these materials for veneers remains experimental.

A systematic review and meta-analysis of the survival of feldspathic porcelain veneers over 5 and 10 years

PURPOSE: This systematic review reports on the survival of feldspathic porcelain veneers.

MATERIALS AND METHODS: The Cochrane Library, MEDLINE (OVID), Embase, Web of Knowledge, selected journals, clinical trials registers, and conference proceedings were searched independently by two reviewers. Academic colleagues were also contacted to identify relevant research. Inclusion criteria were human cohort studies (prospective and retrospective) and controlled trials assessing outcomes of feldspathic porcelain veneers in more than 15 patients and with at least some of the veneers in situ for 5 years. Of 4,294 articles identified, 116 studies underwent full-text screenings and 69 were further reviewed for eligibility. Of these, 11 were included in the qualitative analysis and 6 (5 cohorts) were included in meta-analyses. Estimated cumulative survival and standard error for each study were assessed and used for meta-, sensitivity, and post hoc analyses. The I2 statistic and the Cochran Q test and its associated P value were used to evaluate statistical heterogeneity, with a random-effects meta-analysis used when the P value for heterogeneity was less than .1. Galbraith, forest, and funnel plots explored heterogeneity, publication patterns, and small study biases.

RESULTS: The estimated cumulative survival for feldspathic porcelain veneers was 95.7% (95% confidence interval [CI]: 92.9% to 98.4%) at 5 years and ranged from 64% to 95% at 10 years across three studies. A post hoc meta-analysis indicated that the 10-year best estimate may approach 95.6% (95% CI: 93.8% to 97.5%). High levels of statistical heterogeneity were found.

CONCLUSIONS: When bonded to enamel substrate, feldspathic porcelain veneers have a very high 10-year survival rate that may approach 95%. Clinical heterogeneity is associated with differences in reported survival rates. Use of clinically relevant survival definitions and careful reporting of tooth characteristics, censorship, clustering, and precise results in future research would improve metaanalytic estimates and aid treatment decisions.

Gene-based therapy in prostate cancer

Prostate cancer is one of the commonest causes of illness and death from cancer. Radical prostatectomy, radiotherapy, and hormonal therapy are the main conventional treatments. However, gene therapy is emerging as a promising adjuvant to conventional strategies, and several clinical trials are in progress. Here, we outline several approaches to gene therapy for prostate cancer that have been investigated. Methods of gene delivery are described, particularly those that have commonly been used in research on prostate cancer. We discuss efforts to achieve tissue-specific gene delivery, focusing on the use of tissue-specific gene promoters. Finally, the present use of gene therapy for prostate cancer is evaluated. The ability to deliver gene-therapy vectors directly to prostate tissue, and to regulate gene expression in a tissue-specific manner, offers promise for the use of gene therapy in prostate cancer.

The influence of cyclosporin alone, or cyclosporin and methotrexate, on the incidence of mixed haematopoietic chimaerism following allogeneic sibling bone marrow transplantation for severe aplastic anaemia

We previously reported a randomized trial comparing Cyclosporin-A (CsA) and short-term methotrexate versus CsA alone for graft-versus-host disease (GvHD) prophylaxis in 71 patients undergoing allogeneic haematopoietic stem cell transplantation (HSCT) from a human leucocyte antigen-identical sibling for severe aplastic anaemia (SAA). We found a better survival in the group receiving the two-drug prophylaxis regimen with no significant difference in the probability of developing GvHD between the two groups. The present study details chimaeric analysis and its influence on survival and GvHD occurrence in 45 of the original 71 patients in whom serial samples were available. Analysis was carried out in a blinded prospective manner. Seventy-two per cent achieved complete donor chimaerism (DC), 11% stable mixed chimaerism (SMC) and 17% progressive mixed chimaerism (PMC). The overall 5-year survival probability was 82% (+/-11%) with a significant survival advantage (P = 0.0009) in DC or SMC compared to those with PMC. Chronic GvHD was more frequent in DC patients, whereas no patient with SMC developed chronic GvHD. Graft failure occurred in 50% of the PMC group. This study demonstrates the relevance of chimaerism analysis in patients receiving HSCT for SAA and confirms the occurrence of mixed chimaerism in a significant proportion of recipients.