Evidence for a causal role for vitamin D in multiple sclerosis (MS) is being gathered. Epidemiological, molecular and animal model studies have paved the way in our understanding of the effects of vitamin D in demyelinating disease. Several clinical trials have been completed and more are under way to understand the full extent and value of vitamin D supplementation on disease progression. Many questions remain unanswered however and careful study design is increasingly pertinent. Timing of exposure, dosage and transgenerational effects are some of the several important questions that need to be addressed. In this issue, Carlson and Rose highlight these points and provide a review of vitamin D and MS with an emphasis on the most recent clinical studies. Further evidence of vitamin D deficiency as a causal factor, its molecular targets in MS and its prospect as a therapeutic and preventative agent are questions that warrant further study.
Introduction: IgA nephropathy, the most prevalent glomerular disease in the world, requires a renal biopsy for diagnosis. Reliable biomarkers are needed for the non-invasive diagnosis of this disease and to more fully delineate its natural history and risk for progression. Areas covered: In this review, the authors examine serum levels of galactose-deficient IgA1 (Gd-IgA1) and glycan-specific IgG and IgA autoantibodies that are integral to pathogenesis of IgA nephropathy. They also explore biomarkers related to alternative and lectin pathways of complement activation and serum and urinary peptide biomarkers detected by mass spectrometric methods. The literature search included review of all publications having IgA nephropathy in the title that were cited in PubMed and Scopus over the past 10 years and a non-systematic review of abstracts published for the annual meetings of the American Society of Nephrology and the International Symposia on IgA Nephropathy. Expert opinion: Serum Gd-IgA1 level and glycan-specific autoantibody levels are prime candidates to become diagnostic biomarkers for IgA nephropathy because of their central role in the earliest stages of disease pathogenesis. Assays for serum levels of complement proteins C3 and factor H are readily available in clinical practice and deserve continued study, either alone or in tandem with total serum IgA or serum Gd-IgA1 levels, as prognostic biomarkers for patients with IgA nephropathy. Urinary peptidomic data are also reviewed because this approach can successfully differentiate patients with IgA nephropathy from healthy controls and from patients with other forms of renal disease.
INTRODUCTION:This article provides an overview of actual biomarkers with an impact on improvement of diagnosis and treatment of esophageal cancer patients.AREAS COVERED:Recent literature has been analyzed and provides information regarding the potential role of molecular markers as a diagnostic or prognostic factor in esophageal cancer.EXPERT OPINION:Until now, the role of molecular markers is far from being firmly established for routine use and is not without obstacles. However, with reliable standardized methods, established cut-off values and promising candidates in marker panels with markers of genetic, epigenetic and proteomic origin might result in a marker tool worthwhile of being validated in large, prospective, randomized trials. Novel validated marker combinations have to be clinically applied to prove their putative role in complementing clinical techniques within the development of better detection concepts of esophageal cancer, improving patients' long-term prognosis by early and purposive therapy within individualized treatment concepts.
INTRODUCTION:Kaposi's sarcoma (KS) is a vascular neoplasm with distinct clinical-epidemiological subtypes and varied clinical presentations. While the association of KS with human herpesvirus-8 (HHV8, KSHV) infection is well known, additional factors are needed for tumorigenesis. The precise sequence of events involved in KS development, progression and regression continues to be investigated. The discovery of KSHV biomarkers is helpful for diagnostic purposes, for understanding KS pathogenesis and for identifying potential druggable targets.AREAS COVERED:This article reviews a number of key biomarkers relevant for the diagnosis of KS and HHV8-related pathogenesis. New developments in KS, potential therapeutic targets and the challenges involved in their discovery are highlighted.EXPERT OPINION:Although there is currently no cure for KS, continued research devoted to uncovering biomarkers and understanding their pathogenic roles remains encouraging. The hope is that sometime soon one of these candidate targets will provide a curative therapy for this enigmatic sarcoma.
INTRODUCTION:Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide and this burden is predicted to increase unless exposure to risk factors is addressed. Diagnosis of COPD is a challenge: COPD is underdiagnosed and frequently misdiagnosed for asthma or other respiratory conditions. Although spirometry is only one parameter for establishing a clinical diagnosis of COPD, lack of routine spirometry is a key cause of COPD misdiagnosis. Differential diagnosis from asthma is essential because the treatment strategies for, and progression and outcomes of, the two conditions vary greatly.AREAS COVERED:Here the authors review methods for the differential diagnosis of COPD and asthma; approaches to improve diagnosis, including case-finding and screening; the identification of specific COPD phenotypes and targeted therapy; and the potential role of exhaled biomarkers in the diagnosis of COPD.EXPERT OPINION:Methods to diagnose COPD, specifically differential diagnosis from asthma, have improved in recent years. To translate these into clinical practice will require the development of combined guidelines for COPD and asthma that include COPD-asthma overlap syndrome and are based on evidence from randomized controlled trials.
INTRODUCTION:Skeletal muscle channelopathies are rare disorders of muscle membrane excitability. Their episodic nature may result in diagnostic difficulty and delays in diagnosis. Advances in diagnostic clinical electrophysiology combined with DNA-based diagnosis have improved diagnostic accuracy and efficiency. Ascribing pathogenic status to identified genetic variants in muscle channel genes may be complex and functional analysis, including molecular expression, may help with this. Accurate clinical and genetic diagnosis enables genetic counselling, advice regarding prognosis and aids treatment selection. AREAS COVERED:An approach to accurate and efficient diagnosis is outlined. The importance of detailed clinical evaluation including careful history, examination and family history is emphasised. The role of specialised electrodiagnostics combined with DNA testing and molecular expression is considered. New potential biomarkers including muscle MRI using MRC Centre protocols are discussed. EXPERT OPINION:A combined diagnostic approach using careful clinical assessment, specialised neurophysiology and DNA testing will now achieve a clear diagnosis in most patients with muscle channelopathies. An accurate diagnosis enables genetic counselling and provides information regarding prognosis and treatment selection. Genetic analysis often identifies new variants of uncertain significance. In this situation, functional expression studies as part of a diagnostic service will enable determination of pathogenic status of novel genetic variants.
INTRODUCTION:Vitamin D has attracted a lot of attention in relation to multiple sclerosis (MS) and many other disorders; however, the evidence for a major role(s) for vitamin D in MS is compelling and multifactorial involving results from epidemiology, immunology, genetics, biochemistry and translational medicine.AREAS COVERED:Multiple studies that illustrate that insufficient levels of vitamin D not only contribute to the risk of getting MS but may also worsen disease progression for MS patients are discussed. Genetic evidence also implicates vitamin D as being important in MS since individuals are at greater risk of getting MS if they harbor a mutation in a gene responsible for vitamin D synthesis (25-hydroxylase). Other modifiers of MS disease appear to interact with the vitamin D receptor. The Epstein-Barr virus (EBV) is a risk factor for MS and may in part worsen disease through the interactions between one of its gene products (EBNA-3) and the vitamin D receptor to attenuate vitamin D-regulated genes. Retrospective studies have shown that higher vitamin D levels are associated with a significant improvement of clinical and magnetic resonance imaging outcomes. Increasing clinical observations are also indicating adverse effects of low vitamin D in MS.EXPERT OPINION:Mounting evidence from epidemiology, genetic, retrospective clinical studies and emerging basic science studies support a strong rationale for how vitamin D could be an important modifier of MS disease. Well-designed clinical trials are now ongoing and will provide further insight on how vitamin D supplementation may impact MS.
Introduction: The imaging evaluation of pulmonary nodules, often incidentally detected on imaging examinations performed for other clinical reasons, is a frequently encountered clinical circumstance. With advances in imaging modalities, both the detection and characterization of pulmonary nodules continue to evolve and improve. Areas covered: This article will review the imaging modalities used to detect and diagnose benign and malignant pulmonary nodules, with a focus on computed tomography (CT), which continues to be the mainstay for evaluation. The authors discuss recent advances in the lung nodule management, and an algorithm for the management of indeterminate pulmonary nodules. Expert opinion: There are set of criteria that define a benign nodule, the most important of which are the lack of temporal change for 2 years or more, and certain benign imaging criteria, including specific patterns of calcification or the presence of fat. Although some indeterminate pulmonary nodules are immediately actionable, generally those approaching 1 cm or larger in diameter, at which size the diagnostic accuracy of tools such as positron emission tomography (PET)/CT, single photon emission CT (SPECT) and biopsy techniques are sufficient to warrant their use. The majority of indeterminate pulmonary nodules are under 1 cm, for which serial CT examinations through at least 2 years for solid nodules and 3 years for ground-glass nodules, are used to demonstrate either benign biologic behavior or otherwise. The management of incidental pulmonary nodules involves a multidisciplinary approach in which radiology plays a pivotal role. Newer imaging and postprocessing techniques have made this a more accurate technique eliminating ambiguity and unnecessary follow-up.
Introduction: High-throughput molecular profiling is transforming long-standing conceptions of diffuse gliomas, the most common primary brain tumors. Indeed, comprehensive genomic, transcriptomic and epigenomic analyses have not only provided striking mechanistic insights into the pathogenesis of diffuse gliomas but also greatly enriched the pool of potential biomarkers for prognostic and predictive patient stratification. Areas covered: This article summarizes significant recent developments in the molecular characterization of diffuse gliomas, focusing on implications for biomarker development and application. In doing so, we will also address relevant high-throughput molecular profiling technologies and both the opportunities and challenges implicit in their widespread incorporation into disease management workflows. Expert opinion: Although the number of validated biomarkers guiding diffuse glioma management is currently quite small, rapidly progressing molecular annotation continues to provide a steady stream of clinically relevant candidates, many of which show promise for predictive capabilities in the context of specific targeted therapeutics. Such potential now requires rigorous validation in well-designed clinical trials supported by robust molecular profiling assays operative from standard clinical material.
INTRODUCTION:Fabry disease (FD) is an X-linked disorder of glycosphingolipid metabolism caused by deficiency of the lysosomal enzyme alpha galactosidase A. Clinical features include neuropathic pain, rash, proteinuria renal failure, stroke and cardiomyopathy accompanied by a reduced life expectancy. Patients report an average delay of > 10 years between symptom onset and diagnosis. Newborn screening studies suggest a much higher prevalence than that found on population studies supporting the notion that FD is under-diagnosed.AREAS COVERED:Four key challenges in the diagnosis of FD and strategies to overcome them are discussed. The clinical features of FD are highly heterogeneous resulting in patients presenting to many different specialists, often with non-specific symptoms with a wide differential diagnosis. The pathophysiological mechanisms underlying this are poorly understood and the prediction of pathogenicity on the basis of gene mutation analysis can be problematic. While the availability of treatment adds an impetus to make the correct diagnosis, our understanding of when and if treatment may be required in a specific individual is incomplete.EXPERT OPINION:Improving diagnostic rates of FD requires a greater awareness of the disorder among physicians to whom patients may present, new strategies to determine the pathogenicity of novel mutations and a greater understanding of the natural history of FD across the phenotypic spectrum. Collaborative clinical and laboratory research is vital in furthering knowledge of the underlying mechanisms of this disorder and how they may be impacted by current or future therapies.
Introduction: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with heterogeneous manifestations. Of particular importance for clinicians are the precise assessment of disease activity and the ability to make appropriate therapeutic decisions. Therefore, interest has increased in biomarkers that can be measured as indicators of pathogenic processes, disease activity and response to management. Areas covered: This article introduces well-studied, as well as newly discovered, biomarkers related to SLE, divided into categories for diagnosis, disease activity and organ involvement. Expert opinion: The lack of reliable biomarkers for lupus hampers the assessment of disease activity and impedes the evaluation of treatment response. Although many reports of lupus biomarkers have been published, few longitudinal and interventional studies have validated the utility of any biomarker for monitoring disease activity. Consortiums of investigators will certainly help in recruiting sufficient number of patients and facilitating the development of standardized assays. Moreover, owing to the multifactorial nature of lupus, a multiplexed approach will clearly be essential. Another promising approach is the use of high-throughput technology, including DNA and antibody microarrays, flow cytometry and proteomic techniques.
OBJECTIVESelf-monitoring of blood glucose is a key element in diabetes management. Accurate and precise performance of blood glucose monitors (BGMs) ensures that valid values are obtained to guide treatment decisions by patients and physicians. BGStar and iBGStar are hand-held BGMs that use dynamic electrochemistry to correct for potential interferences and thereby minimize system errors.RESEARCH DESIGN AND METHODSA single-center, in vitro diagnostic device performance evaluation with heparinized oxygenated venous blood samples (intra-assay precision) and control solutions (interassay precision) was performed in a laboratory setting, comparing BGStar and iBGStar with 12 competitors.MAIN OUTCOME MEASURESThe primary outcome was the coefficient of variation percent (CV%) of the BGMs investigated.RESULTSIn inter-assay precision analyses, all but GlucoMen LX had a CV <5%, and in intra-assay precision analyses, 10 of the 14 devices tested had CV <5%. BGStar and iBGStar had a CV <5% in both the inter- and intra-assay precision analyses. The smallest variation was found in the near-normoglycemic glucose range (5.3 - 8.0 mmol/l) for both BGStar and iBGStar in the inter-assay precision analysis.CONCLUSIONSBGStar and iBGStar were proven to have very good inter-assay and high intra-assay precision, demonstrating low scattering of replicate measurements with both clinical samples and control solutions.
Coeliac disease is an autoimmune condition resulting from an abnormal reaction to dietary gluten leading to small bowel villous atrophy. International prevalence studies suggest that coeliac disease affects 1% of the adult population. However, despite its high prevalence, large numbers of patients go undiagnosed. One method of increasing detection rates would be to introduce a quick screening test in the form of a finger-prick blood test.There are currently four available point-of-care tests (POCTs) available for use by health professionals. This diagnostic evaluation will review the evidence for the use of POCTs in coeliac disease including Simtomax a novel test for deamidated gliadin peptides and total IgA level.An accurate POCT has the potential to increase the rates of diagnosis of coeliac disease if used effectively as part of a case finding approach in primary or secondary care. Evidence for the use of Simtomax is currently fairly limited only drawing comparison with laboratory serology rather than the gold standard of histology and it has only been trialled in high-risk populations. However, results to date are encouraging and further research into this area is required.
INTRODUCTION:The worldwide incidence of biliary tract carcinoma (BTC, tumours of the bile ducts and gall-bladder) continues to rise, with the only potentially curative treatment remaining surgical resection or transplantation, possible in only a minority of patients. Late presentation and a paucity of effective treatments mandate the development of techniques for early lesion detection.AREAS COVERED:This article reviews currently available biomarkers for the diagnosis and prognosis of BTC, as well as recently published studies describing novel serum, bile and urinary biomarkers.EXPERT OPINION:The incorporation of novel analysis techniques, such as digital image analysis and fluorescence in situ hybridization, into existing management algorithms enhances the accuracy of brush cytology taken at the time of therapeutic endoscopy. However, a key goal is the discovery of reliable non-invasive biomarkers with high sensitivity and specificity. Recent advances in gene sequencing and expression, clonal evolution and tumour heterogeneity in other cancers should advance understanding of BTC tumour biology and facilitate biomarker discovery.
INTRODUCTIONBiochemical diagnosis of acromegaly relies on measurement of insulin-like growth factor-1 (IGF-1) and growth hormone (GH). An elevated IGF-1 level above the age- and gender-specific normal range and nonsuppression of GH to oral glucose load to a nadir < 0.4 ng/ml in sensitive assays are currently considered diagnostic of acromegaly. Lack of normative data for both IGF-1 and GH across a wide range of populations and ethnicities, interassay and intraassay laboratory variability, pulsatility of GH secretion, and effects of medications and hormones may confound interpretation of these biochemical tests.AREAS COVEREDClinical situations in which acromegaly should be suspected and/or investigated. Strengths and limitations of current IGF-1/GH assays are discussed. Clinical scenarios with discordant GH suppression test and IGF-1 levels and, briefly, acromegaly in pregnancy, prolactin-cosecreting tumors, familial acromegaly, and nonpituitary acromegaly are also discussed.EXPERT OPINIONSerum IGF-1 is the cornerstone and in most cases the stand-alone test in the diagnosis and follow-up in patients with acromegaly. Diagnosis depends on the accurate and reliable measurement of serum IGF-1. GH suppression testing is currently used in limited clinical setting. Standardization of IGF-1 assay and development of normative data across a wide population base are needed. Newer bioassays for IGF-1 hold promise for future.
BACKGROUND:Women suspecting pregnancy need an accurate result when they conduct a home pregnancy test. A variety of tests are available from simple professional style strips to midstream tests with a digitally displayed result. However, it is not known whether all these formats can be used and read correctly by untrained women.OBJECTIVES:The aim of this study is to evaluate usability and reading accuracy of home pregnancy test formats.METHODS:Female volunteers, 18 - 45 years (Manchester, UK) completed questionnaires on their home-use experience of six pregnancy tests (strip, cassette, midstream visual and digital formats). These volunteers then evaluated device results using hCG-urine standards at a study centre, thereafter completing a questionnaire and ranking evaluation.RESULTS:Data were available from 111 volunteers. Women preferred midstream test formats; > 70% scored branded midstream digital and easy-use visual tests as 1or 2 (7-point Likert score), compared with ∼ 30% for store-brand and branded midstream visual tests, and < 10% for cassette or strip tests. Many cassette tests (23%) failed to provide a result (4, ≤ 2% for strips, midstream, respectively). Volunteers disagreed with study co-ordinator reading of test results in 30 and 40% of cases for the cassette and strip test results, respectively, compared with < 3% when using midstream digital or easy-use visual tests. Volunteers preferred the branded midstream digital, followed by branded midstream easy-use and visual tests.CONCLUSIONS:In this study, the branded midstream digital test was superior to other tests evaluated and fulfilled the criteria of being an easy-to-use and interpret test; strip and cassette tests showed poor performance in women's hands.
INTRODUCTION:Computed tomography (CT) has become key for patient management due to its outstanding capabilities for detecting disease processes and assessing treatment response, which has led to expansion in CT imaging for diagnostic and image-guided therapeutic interventions. Despite these benefits, the growing use of CT has raised concerns as radiation risks associated with radiation exposure. AREAS COVERED:The purpose of this article is to familiarize the reader with fundamental concepts of dose metrics for assessing radiation exposure and weighting radiation-associated risks. The article also discusses general approaches for reducing radiation dose while preserving diagnostic quality. The authors provide additional insight for undertaking protocol optimization, customizing scanning techniques based on the patients' clinical scenario and demographics. Supplemental strategies are postulated using more advanced post-processing techniques for achieving further dose improvements. EXPERT OPINION:The technologic offerings of CT are integral to modern medicine and its role will continue to evolve. Although, the estimated risks from low levels of radiation of a single CT exam are uncertain, it is prudent to minimize the dose from CT by applying common sense solutions and using other simple strategies as well as exploiting technologic innovations. These efforts will enable us to take advantage of all the clinical benefits of CT while minimizing the likelihood of harm to patients.
INTRODUCTION:Heart failure with preserved ejection fraction (HFPEF) is a common syndrome, accounting for about 50% of all patients with heart failure (HF). Morbidity and mortality are similar to patients with HF with reduced ejection fraction (HFREF), yet no effective treatment has been identified in randomized clinical trials.AREAS COVERED:This article provides an overview of the available literature regarding diagnosing established HFPEF and potential new therapeutic targets for the early diagnosis of HFPEF. Vascular dysfunction, ventricular-arterial coupling, oxidative stress, extracellular matrix regulation, chronotropic incompetence, pulmonary hypertension, exercise testing and biomarkers were taken into consideration next to conventional measurements of diastolic dysfunction.EXPERT OPINION:Measuring diastolic dysfunction in HFPEF is considered important in many patients. Nevertheless, today we know that other causes besides diastolic dysfunction are also involved in the pathophysiology of many HFPEF patients and need to be investigated in order to make a correct diagnosis. Therefore, further research is required to allow better and more specific diagnostic and treatment options to reduce the morbidity and mortality for this ever-expanding HF population.
Personalized medicine based on tumor characteristics is transforming the management of lung cancer. This review provides an overview of clinically approved strategies to personalize treatment for lung cancer as well as evolving strategies in various stages of clinical development.Selecting therapy based on various tumor characteristics such as histology and presence of specific molecular alterations will be covered. This review will not only discuss the role of targeted agents in personalizing care for lung cancer but also the strategies to personalize traditional chemotherapeutic agents.Advances in genomic medicine to identify key genetic alterations with subsequent development of matching targeted agents are rapidly changing the management of lung cancer. Being able to target key driver molecular aberrations is certainly exciting and clinically meaningful, but only for a limited period of time. Intra- and intertumoral heterogeneity is a major contributor to therapy resistance, a substantial roadblock to durable response. Better understanding of resistance mechanism is at least as important as identifying new targetable genetic changes to effectively advance personalized therapy for lung cancer. Finally, optimization of biopsy specimens and rigorous validation steps to ensure reliability of diagnostic methods would be critical in moving forward.
