Incidence of unilateral arm lymphoedema after breast cancer : a systematic review and meta-analysis

Background The body of evidence related to breast-cancer-related lymphoedema incidence and risk factors has substantially grown and improved in quality over the past decade. We assessed the incidence of unilateral arm lymphoedema after breast cancer and explored the evidence available for lymphoedema risk factors. Methods We searched Academic Search Elite, Cumulative Index to Nursing and Allied Health, Cochrane Central Register of Controlled Trials (clinical trials), and Medline for research articles that assessed the incidence or prevalence of, or risk factors for, arm lymphoedema after breast cancer, published between January 1, 2000, and June 30, 2012. We extracted incidence data and calculated corresponding exact binomial 95% CIs. We used random effects models to calculate a pooled overall estimate of lymphoedema incidence, with subgroup analyses to assess the effect of different study designs, countries of study origin, diagnostic methods, time since diagnosis, and extent of axillary surgery. We assessed risk factors and collated them into four levels of evidence, depending on consistency of findings and quality and quantity of studies contributing to findings. Findings 72 studies met the inclusion criteria for the assessment of lymphoedema incidence, giving a pooled estimate of 16·6% (95% CI 13·6–20·2). Our estimate was 21·4% (14·9–29·8) when restricted to data from prospective cohort studies (30 studies). The incidence of arm lymphoedema seemed to increase up to 2 years after diagnosis or surgery of breast cancer (24 studies with time since diagnosis or surgery of 12 to <24 months; 18·9%, 14·2–24·7), was highest when assessed by more than one diagnostic method (nine studies; 28·2%, 11·8–53·5), and was about four times higher in women who had an axillary-lymph-node dissection (18 studies; 19·9%, 13·5–28·2) than it was in those who had sentinel-node biopsy (18 studies; 5·6%, 6·1–7·9). 29 studies met the inclusion criteria for the assessment of risk factors. Risk factors that had a strong level of evidence were extensive surgery (ie, axillary-lymph-node dissection, greater number of lymph nodes dissected, mastectomy) and being overweight or obese. Interpretation Our findings suggest that more than one in five women who survive breast cancer will develop arm lymphoedema. A clear need exists for improved understanding of contributing risk factors, as well as of prevention and management strategies to reduce the individual and public health burden of this disabling and distressing disorder.

Applying the ecological model of behavior change to a physical activity trial in retirement communities : description of the study protocol

Objectives To describe the intervention protocol for the first multilevel ecological intervention for physical activity in retirement communities that addresses individual, interpersonal and community influences on behavior change. Design A cluster randomized controlled trial design was employed with two study arms: a physical activity intervention and an attention control successful aging condition. Setting Sixteen continuing care retirement communities in San Diego County. Participants Three hundred twenty older adults, aged 65 years and older, are being recruited to participate in the trial. In addition, peer leaders are being recruited to lead some study activities, especially to sustain the intervention after study activities ceased. Intervention Participants in the physical activity trial receive individual, interpersonal and community intervention components. The individual level components include pedometers, goal setting and individual phone counseling. The interpersonal level components include group education sessions and peer-led activities. The community level components include resource audits and enumeration, tailored walking maps, and community improvement projects. The successful aging group receives individual and group attention about successful aging topics. Measurements The main outcome is light to moderate physical activity, measured objectively by accelerometry. Other objective outcomes included physical functioning, blood pressure, physical fitness, and cognitive functioning. Self report measures include depressive symptoms and health related quality of life. Results The intervention is being delivered successfully in the communities and compliance rates are high. Conclusion Ecological Models call for interventions that address multiple levels of the model. Previous studies have not included components at each level and retirement communities provide a model environment to demonstrate how to implement such an intervention.

Comparison of three different dressings for partial thickness burns in children : study protocol for a randomised controlled trial

BACKGROUND: In the paediatric population, pain and distress associated with burn injuries during wound care procedures remain a constant challenge. Although silver dressings are the gold standard for burn care in Australasia, very few high-level trials have been conducted that compare silver dressings to determine which will provide the best level of care clinically. Therefore, for paediatric patients in particular, identifying silver dressings that are associated with lower levels of pain and rapid wound re-epithelialisation is imperative. This study will determine whether there is a difference in time to re-epithelialisation and pain and distress experienced during wound care procedures among Acticoat, Acticoat combined with Mepitel and Mepilex Ag dressings for acute, paediatric partial thickness burns. METHODS/DESIGN: Children aged 0 to 15 years with an acute partial thickness (superficial partial to deep partial thickness inclusive) burn injury and a burn total body surface area of Clinical Trials Registry ACTRN12613000105741.

Diabetes mellitus in South Asia : scientific evaluation of the research output

BACKGROUND: Diabetes in South Asia represents a different disease entity in terms of its onset, progression, and complications. In the present study, we systematically analyzed the medical research output on diabetes in South Asia. METHODS: The online SciVerse Scopus database was searched using the search terms "diabetes" and "diabetes mellitus" in the article Title, Abstract or Keywords fields, in conjunction with the names of each regional country in the Author Affiliation field. RESULTS: In total, 8478 research articles were identified. Most were from India (85.1%) and Pakistan (9.6%) and the contribution to the global diabetes research output was 2.1%. Publications from South Asia increased markedly after 2007, with 58.7% of papers published between 2000 and 2010 being published after 2007. Most papers were Research Articles (75.9%) and Reviews (12.9%), with only 90 (1.1%) clinical trials. Publications predominantly appeared in local national journals. Indian authors and institutions had the most number of articles and the highest h-index. There were 136 (1.6%) intraregional collaborative studies. Only 39 articles (0.46%) had >100 citations. CONCLUSIONS: Regional research output on diabetes mellitus is unsatisfactory, with only a minimal contribution to global diabetes research. Publications are not highly cited and only a few randomized controlled trials have been performed. In the coming decades, scientists in the region must collaborate and focus on practical and culturally acceptable interventional studies on diabetes mellitus.

IL-23R is epigenetically regulated and modulated by chemotherapy in non-small cell lung cancer

The Interleukin-23 (IL-23)/IL-23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of IL-17. Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the IL-23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the IL-23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of IL-23 and IL-12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the IL-23/IL-23R axis in this disease.

Epigenetic regulation of chemokine/chemokine receptor expression

Epigenetic regulation of gene expression is an important event for normal cellular homeostasis. Gene expression may be "switched" on or "turned" off via epigenetic means through adjustments in DNA architecture. These structural alterations result from changes to the DNA methylation status in addition to histone posttranslational modifications such as acetylation and methylation. Drugs which can alter the status of these epigenetic markers are currently undergoing clinical trials in a wide variety of diseases, including cancer.We illustrate the treatment of cell lines with histone deacetylase (HDi) and DNA methyltransferase inhibitors and the subsequent RNA isolation and reverse transcriptase polymerase chain reaction for several members of the CXC (ELR(+)) chemokine family. In addition we describe a chromatin immunoprecipitation assay to determine the association between chromatin transcription markers and DNA following pretreatment of cell cultures with an HDi, Trichostatin A (TSA). This assay allows us to determine whether treatment with TSA dynamically remodels the promoter region of our selected genes, as judged by the differences in the PCR product between our treated and untreated samples.

The role of the arachidonic acid pathway in NSCLC development and progression : novel approaches for therapeutic intervention

Arachidonic acid metabolism through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P-450 epoxygenase (EPOX) pathways is responsible for the formation of biologically active eicosanoids, including prostanoids, leukotrienes, hydroxyeicosatetraenoic acid, epoxyeicosatrienoic acid and hydroperoxyeicosatetraenoic acids. Altered eicosanoid expression levels are commonly observed during tumour development and progression of a range of malignancies, including non-small cell lung cancer (NSCLC). Arachidonic acid-derived eicosanoids affect a range of biological phenomena to modulate tumour processes such as cell growth, survival, angiogenesis, cell adhesion, invasion and migration and metastatic potential. Numerous studies have demonstrated that eicosanoids modulate NSCLC development and progression, while targeting these pathways has generally been shown to inhibit tumour growth/progression. Modulation of these arachidonic acid-derived pathways for the prevention and/or treatment of NSCLC has been the subject of significant interest over the past number of years, with a number of clinical trials examining the potential of COX and LOX inhibitors in combination with traditional and novel molecular approaches. However, results from these trials have been largely disappointing. Furthermore, enthusiasm for the use of selective COX-2 inhibitors for cancer prevention/treatment waned, due to their association with adverse cardiovascular events in chemoprevention trials. While COX and LOX targeting may both retain promise for NSCLC prevention and/or treatment, there is an urgent need to understand the downstream signalling mechanisms through which these and other arachidonic acid-derived signalling pathways mediate their effects on tumourigenesis. This will allow for development of safer and potentially more effective strategies for NSCLC prevention and/or treatment. Chemoprevention studies with PGI2 analogues have demonstrated considerable promise, while binding to/signalling through PGE2 receptors have also been the subject of interest for NSCLC treatment. In this chapter, the role of the eicosanoid signalling pathways in non-small cell lung cancer will be discussed. In particular, the effect of the eicosanoids on tumour cell proliferation, their roles in induction of cell death, effects on angiogenesis, migration, invasion and their regulation of the immune response will be assessed, with signal transduction pathways involved in these processes also discussed. Finally, novel approaches targeting these arachidonic acid-derived eicosanoids (using pharmacological or natural agents) for chemoprevention and/or treatment of NSCLC will be outlined. Elucidating the molecular mechanisms underlying the effects of specific or general arachidonic acid pathway modulators may lead to the design of biologically and pharmacologically targeted therapeutic strategies for NSCLC prevention/treatment, which may be used alone or in combination with conventional therapies.

Targeted therapies in non-small cell lung cancer

The majority of non-small cell lung cancer (NSCLC) patients present with advanced disease and with a 5 year survival rate of <15% for these patients, treatment outcomes are considered extremely disappointing. Standard chemotherapy regimens provide some improvement to ~40% of patients. However, intrinsic and acquired chemoresistance are a significant problem and hinder sustained long term benefits of such treatments. Advances in proteomic and genomic profiling have increased our understanding of the aberrant molecular mechanisms that are driving an individual's tumour. The increased sensitivity of these technologies has enabled molecular profiling at the stage of initial biopsy thus paving the way for a more personalised approach to the treatment of cancer patients. Improvements in diagnostics together with a wave of new targeted small molecule inhibitors and monoclonal antibodies have revolutionised the treatment of cancer. To date there are essentially three targeted agents approved for clinical use in NSCLC. The tyrosine kinase inhibitor (TKI) erlotinib, which targets the epidermal growth factor receptor (EGFR) TK domain, has proven to be an effective treatment strategy in patients who harbour activating mutations in the EGFR TK domain. Bevacizumab a monoclonal antibody targeting the vascular endothelial growth factor (VEGF) can improve survival, response rates, and progression-free survival when used in combination with chemotherapy. Crizotinib, a small-molecule drug, inhibits the tyrosine kinase activity of the echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase (EML4-ALK) fusion protein, resulting in decreased tumour cell growth, migration, and invasiveness in patients with locally advanced or metastatic NSCLC. The clinical relevance of several other targeted agents are under investigation in distinct molecular subsets of patients with key "driver" mutations including: KRAS, HER2, BRAF, MET, PIK3CA, AKT1,MAP2K1, ROS1 and RET. Often several pathways are activated simultaneously and crosstalk between pathways allows tumour cells to escape the inhibition of a single targeted agent. This chapter will explore the clinical development of currently available targeted therapies for NSCLC as well as those in clinical trials and will examine the synergy between cytotoxic therapies.

Acticoat™ : A cost-effective and evidence-based dressing strategy [Letter to the Editor]

We thank Dr. Burd et al. for taking an interest in our paper [1]. The retrospective cohort study was performed and published for two reasons. Firstly, we wished to compare and contrast the use of Acticoat™ and Silvazine™, and secondly we wished to demonstrate how one's practice can be dramatically altered by a change in dressing used. We found that Acticoat™ was safe and easy to use, caused less trauma to patients, required less frequent dressing changes and enabled treatment to be conducted on an outpatient, rather than an inpatient basis. During the period of Acticoat™ treatment we also saw a dramatic reduction in grafting requirements and also in the need for long-term scar management. Burd et al. correctly state that silver-based dressings are now more widely available, however many burn centres in the world continue to use silver sulphadiazine with daily baths. We therefore feel that a comparison is very relevant and useful. Prospective, randomised clinical trials of a range of silver-based dressings would indeed be useful, and hopefully Dr. Burd and colleagues will take up their own suggestion and perform these studies...

The changing performance of multifocal contact lenses compared to monovision.

Purpose:Multifocal contact lenses (MCLs) have been available for decades. A review of the literature suggests that while, historically, these lenses have been partially successful, they have struggled to compete with monovision (MV). More recent publications suggest that there has been an improvement in the performance of these lenses. This study set out to investigate whether the apparent improved lens performance reported in the literature is reflected in clinical practice. Methods:Data collected over the last 5yrs via the International Contact Lens Prescribing Survey Consortium was reviewed for patients over the age of 45yrs. The published reports of clinical trials were reviewed to assess lens performance over the time period. Results:Data review was of 16,680 presbyopic lens fits in 38 countries. The results are that 29% were fit with MCLs, 8% MV and 63% single vision (SV). A previous survey conducted in Australia during 1988-89 reported that 9% of presbyopes were fit with MCLs, 29% MV and 63% SV. The results from our survey for Australia alone were 28% (MV 13%) vs 9% (MV 29%) suggesting an increase in usage of MCLs from 1988-89 to 2010. A review of the literature indicates the reported level of visual acuities with MCLs in comparison to MV has remained equivalent over this time period, yet preference has switch from MV to MCLs. Conclusions:There is evidence that currently more MCLs than MV are being fit to presbyopes, compared to 1988-89. This increased use is likely due to the improved visual performance of these lenses, which is not demonstrated with acuity measures but reported by wearers, suggesting that patient-based subjective ratings are currently the best way to measure visual performance.

Oxygen; my view

Oxygen has been the “holy grail” of contact lens wear for over 100 years, but it is just one piece of a complex jigsaw puzzle. Clearly, high oxygen transmissibility (Dk/t) silicone hydrogel lenses meet the oxygen needs of the cornea. The Dk/t of these lenses is over 75 Dk units, which is far above that of the “best” hydrogel lenses (30 Dk units). Clinical trials have failed to reveal any hypoxic problemswith silicone hydrogel lenses. Thus, conditions such as epithelial microcysts, limbal redness, hypoxic staining, stromal neovascularisation, oedema and endothelial polymegethism do not occur with these lenses. My view is that – looking at the “big picture” – we are far better off now that we have silicone hydrogel lenses.

Antibody-based immunotherapy for ovarian cancer: where are we at?

Cytoreductive surgery and chemotherapy continue to be the mainstay of ovarian cancer treatment. However, as mortality from advanced ovarian cancer remains very high, novel therapies are required to be integrated into existing treatment regimens. Immunotherapy represents an alternative and rational therapeutic approach for ovarian cancer based on a body of evidence supporting a protective role of the immune system against these cancers, and on the clinical success of immunotherapy in other malignancies. Whether or not immunotherapy will have a role in the future management of ovarian cancer is too early to tell, but research in this field is active. This review will discuss recent clinical developments of selected immunotherapies for ovarian cancer which fulfil the following criteria: (i) they are antibody-based, (ii) target a distinct immunological pathway, and (iii) have reached the clinical trial stage. Specifically, the focus is on Catumaxomab (anti-EpCAM × anti-CD3), Abagovomab, Oregovomab (anti-CA125), Daclizumab (anti-CD25), Ipilimumab (anti-CTLA-4), and MXD-1105 (anti-PD-L1). Catumaxomab has reached phase III clinical trials and exhibits promise with reports, showing that it can cause a significant and sustained reduction in ascites. Phase I–III clinical trials continue to be conducted on the other antibodies, some of which have had encouraging reports. We will also provide our perspective on the future of immunotherapy for ovarian cancer, and how it may be best employed in treatment regimens.

Transforming the future of treatment for ovarian cancer

As for many other cancers, metastasis is the leading cause of death of patients with ovarian cancer. Vigorous basic and clinical research is being performed to initiate more efficacious treatment strategies to improve the poor outcome of women with this cancer. Current treatment for ovarian cancer includes advanced cyto-reductive surgery and traditional platinum and taxane combined chemotherapy. Clinical trials using novel cytotoxic reagents and tyrosine kinase inhibitors have also been progressing. In parallel, the application of robust unbiased high throughput research platforms using transcriptomic and proteomic approaches has identified that not only individual cell signalling pathways, but a network of molecular pathways, play an important role in the biology of ovarian cancer. Furthermore, intensive genomic and epigenetic analyses have also revealed single nucleotide polymorphisms associated with risk and/or aetiology of this cancer including patient response to treatment. Taken together, these approaches, that are advancing our understanding, will have an impact on the generation of new therapeutic approaches and strategies for improving the outcome and quality of life of patients with ovarian cancer in the near future.

BRAF inhibitor therapy for melanoma, thyroid and colorectal cancers : development of resistance and future prospects

BRAF is a major oncoprotein and oncogenic mutations in BRAF are found in a significant number of cancers, including melanoma, thyroid cancer, colorectal cancer and others. Consequently, BRAF inhibitors have been developed as treatment options for cancers with BRAF mutations which have shown some success in improving patient outcomes in clinical trials. Development of resistance to BRAF kinase inhibitors is common, however, and overcoming this resistance is an area of significant concern for clinicians, patients and researchers alike. In this review, we identify the mechanisms of BRAF kinase inhibitor resistance and discuss the implications for strategies to overcome this resistance in the context of new approaches such as multi-kinase targeted therapies and emerging RNA interference based technologies.

A review of the profile of endothelin axis in cancer and its management

The endothelins and their associated receptors are important controllers of vascular growth, inflammation and vascular tone. In cancer, they have roles in the control of numerous factors in cancer development and progression, including angiogenesis, stromal reaction, epithelial mesenchymal transitions, apoptosis, invasion, metastases and drug resistance. Also, we consider current information on the role of this signalling system in cancer and examine the state of the current cell, animal and clinical trials utilizing endothelin targeted drugs for cancer management. Although targeting the endothelin axis in cell lines and xenografts show some promise in retarding cellular growth, results from limited clinical trials in prostatic cancer are less encouraging and did not offer significant survival benefit. The ability to target both cancer cells and vasculature via endothelin is an important consideration that necessitates the further refining of therapeutic strategies as we continue to explore the possibilities of the endothelin axis in cancer treatment.