Prognostic biomarkers in colorectal cancer: where do we stand?

Colorectal cancer remains a major cause of cancer-related death worldwide. One way to reduce its staggering mortality rate and socio-economic burden is to predict outcome based on the aggressiveness of the tumor biology in order to treat patients accordingly to their risk profile. As such, it comes as no surprise that prognostic biomarker discovery is a hot topic in colorectal cancer research. The last two decades have literally produced tons of new data and an avalanche of potential clinically applicable biomarkers. This review explores and summarizes data concerning the prognostic strength and clinical utility of current and future tissue biomarkers in the diagnosis and treatment of colorectal cancer.     

Peptide-based vaccination: where do we stand?

PURPOSE OF REVIEW: Allergen-specific immunotherapy represents the only causative approach towards allergy treatment. Specific immunotherapy can, however, include allergic reactions and occasionally life-threatening anaphylaxis. Peptides have been evaluated as a potential therapeutic approach in atopic allergic disease because they have the potential to inhibit T-cell function but not induce anaphylaxis. RECENT FINDINGS: Data from early clinical trials of peptide vaccination revealed that therapy was associated with a modest improvement in allergic disease, and was accompanied by a high frequency of adverse reactions. More recent studies have demonstrated improved clinical outcomes, improved safety, and have defined the mechanisms of adverse events observed in earlier studies. Mechanisms of peptide vaccination include the hyporesponsiveness of allergen-specific responses and the induction of regulatory T cells and cytokines. Novel peptide design has allowed the generation of fragments that contain T-cell stimulatory epitopes, lack B cell epitopes, and can induce protective IgG responses in both mice and humans. Other approaches have focused on hypoallergenic B-cell epitopes that induce inhibitory IgG antibodies. Peptides that specifically induce regulatory cytokine production would also enhance peptide vaccines. Several recent studies have described immunodominant epitopes from major allergens that may form candidate peptides for use in peptide vaccination. SUMMARY: The manipulation of peptide epitopes may provide a strategy for the rational design of peptide allergy vaccines further improving safety and efficacy.     

Active surveillance in prostate cancer management: where do we stand now?

Prostate cancer (PCa) is the most common cancer in men, with a steadily rising incidence, affecting on average one in six men during their lifetime. The increase in morbidity is related to the increasing overall life expectancy, prostate-specific antigen testing, implementation of new molecular markers for cancer detection and the more frequent application of multiparametric magnetic resonance imaging. There is growing evidence demonstrating that active surveillance (AS) is an alternative to immediate intervention in patients with very low- and low-risk prostate cancer. Ongoing reports from multiple studies have consistently demonstrated a very low rate of metastases and prostate cancer specific mortality in selected cohorts of patients. As a matter of fact, AS has been adopted by many institutions as a safe and effective management strategy. The aim of our review is to summarize the contemporary data on AS in patients affected with PCa with the intention to present the most clinically useful and pertinent AS protocols.     

Microbiome studies in urology- where do we stand and where can we reach?

The role of microbiome milieu in the urinary tract, their interplay in diverse urological conditions and their therapeutic implications are not completely understood. The microbiome has contributed towards urinary tract infections, urolithiasis and urological cancers. The possibility of manipulating microbiome for diagnosis and treatment is evolving. Probiotics might help in overcoming the problems of recurrent infection and antibiotic resistance. Novel applications like stents and catheters coated with non-pathogenic organisms are being developed. Research in the urinary microbiome has progressed from using mouse models to the presently available three- dimensional cultured organoids, thus making it more feasible. As our knowledge regarding the urinary microbiome increases, justice can be done to many patients in whom the advancements can be used for prophylaxis, diagnosis, treatment and even in improving their quality of life. The growing amount of antibiotic resistance is also a matter of concern and probiotics might be the answer to this upcoming calamity. In this review, we have discussed the role of the urinary microbiome in pathogenesis, diagnosis and treatment of urological conditions and pondered upon its future prospects.     

Prediction of breast cancer metastasis by genomic profiling: where do we stand?

Current concepts conceive “breast cancer” as a complex disease that comprises several very different types of neoplasms. Nonetheless, breast cancer treatment has considerably improved through early diagnosis, adjuvant chemotherapy, and endocrine treatments. The limited prognostic power of classical classifiers determines considerable over-treatment of women who either do not benefit from, or do not at all need, chemotherapy. Several gene expression based molecular classifiers (signatures) have been developed for a more reliable prognostication. Gene expression profiling identifies profound differences in breast cancers, most probably as a consequence of different cellular origin and different driving mutations and can therefore distinguish the intrinsic propensity to metastasize. Existing signatures have been shown to be useful for treatment decisions, although they have been developed using relatively small sample numbers. Major improvements are expected from the use of large datasets, subtype specific signatures and from the re-introduction of functional information. We show that molecular signatures encounter clear limitations given by the intrinsic probabilistic nature of breast cancer metastasis. Already today, signatures are, however, useful for clinical decisions in specific cases, in particular if the personal inclination of the patient towards different treatment strategies is taken into account.     

Two decades of supertasting: where do we stand?

Oral chemosensation can vary greatly across individuals, both in terms of the lowest concentration that can be detected (threshold) and in the magnitude of perceived intensity for stimuli at higher concentrations (suprathreshold response). Individuals who experience greater taste intensity are often termed supertasters, and this phenotype has typically been measured via the suprathreshold bitterness of the tastant propylthiouracil (PROP). Notably, supertasting extends beyond bitterness and other tastants to include oral somatosensation and retronasal olfaction, and it may also include finer acuity as well. Here, we describe the evolution of the supertasting concept over the last 20 years, and summarize the current state of the field. Alternative phenotyping approaches that are not dependent on PROP are reviewed, and the molecular genetics of broadly tuned heightened taste and orosensory response are discussed. We conclude by initiating a conversation on nomenclature as we look toward the next 20 years of chemosensory research.     

Immune mechanisms and immuno -therapy in sepsis:where do we stand ?

Immune mechanisms and immuno -therapy in sepsis:where do we stand ?     

Uncontrolled allergic rhinitis and chronic rhinosinusitis: where do we stand today?

State‐of‐the‐art documents like ARIA and EPOS provide clinicians with evidence‐based treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS), respectively. The currently available medications can alleviate symptoms associated with AR and RS. In real life, a significant percentage of patients with AR and CRS continue to experience bothersome symptoms despite adequate treatment. This group with so‐called severe chronic upper airway disease (SCUAD) represents a therapeutic challenge. The concept of control of disease has only recently been introduced in the field of AR and CRS. In case of poor control of symptoms despite guideline‐directed pharmacotherapy, one needs to consider the presence of SCUAD but also treatment‐related, diagnosis‐related and/or patient‐related factors. Treatment‐related issues of uncontrolled upper airway disease are linked with the correct choice of treatment and route of administration, symptom‐oriented treatment and the evaluation of the need for immunotherapy in allergic patients. The diagnosis of AR and CRS should be reconsidered in case of uncontrolled disease, excluding concomitant anatomic nasal deformities, global airway dysfunction and systemic diseases. Patient‐related issues responsible for the lack of control in chronic upper airway inflammation are often but not always linked with adherence to the prescribed medication and education. This review is an initiative taken by the ENT section of the EAACI in conjunction with ARIA and EPOS experts who felt the need to provide a comprehensive overview of the current state of the art of control in upper airway inflammation and stressing the unmet needs in this domain.     

Serum hepcidin assay in 2011: where do we stand?

The characterization of hepcidin and of its role in iron metabolism in 2001 has entirely modified our understanding of the pathogenesis of iron-linked disorders. Clinical applications related to hepcidin are numerous, and involve iron-overload diseases, anemia, renal disease, chronic inflammation or cancer. Thus, new avenues have emerged from the discovery of this 25 aminoacid peptide and numerous diagnostic and therapeutic tools have been developed and described in the past 10 years. In particular, various methods for accurate quantification of hepcidin in urine and serum have been published but development of a reliable assay is quite a challenging task because, in particular, of inherent properties of the peptide's structure and its low immunogenicity. Thus, the different methods described so far show high variability, in terms of quantitative value of hepcidin measured, specificity and sensitivity. Comparison of these methods has been recently described in a "Round Robin" study, in order to harmonise hepcidin assays and to improve and standardise the available detection/quantification tests. This article focuses on the molecular mechanisms of hepcidin regulation and reviews the various methods of hepcidin quantification, describing the advantages and limitations of each one of them.     

Sjögren's syndrome: Where do we stand,and where shall we go?

Primary Sjögren's syndrome (pSS) is one of the most frequent autoimmune systemic diseases, mainly characterized by ocular and oral dryness due to the progressive destruction of lachrymal and salivary glands by an inflammatory process. A noteworthy proportion of patients also features extraglandular manifestations, sometimes severe and life-threatening. Until now, its management relies mostly on symptomatic interventions, long-term monitoring, and, in patients with severe systemic complications, immunosuppressive drugs can be provided. However, recent years have seen great progresses in the understanding of the pathological processes of the disease. The central role of regulatory lymphocytes, the implication of the type 1 interferon pathway in some patients or the importance of epigenetics have been highlighted. New classification criteria have been recently published and have shed in light an international attempt for a better recognition of the patients, probably thanks to the development of new diagnostic procedures such as salivary gland ultrasonography. To facilitate the detection of treatment efficacy in clinical trials and to help in determining which subgroups of patients would have benefits from intensive therapies, a better definition of activity scores and the availability of new prognostic markers are urgent. Thereby, the development of future therapies should be based on specific molecular signatures that will enable a personalized management of each patient. This review focuses on the most striking advances in the fields of pathophysiology, diagnosis and treatment of pSS, which generate a great hope for pSS patients.     

Laboratory diagnosis of thrombophilic states: where do we stand?

Until recently the laboratory diagnosis of thrombophilia consisted on investigation of the plasmatic anticoagulant pathways and the search for dysfibrinogenemia and antiphospholipid antibodies/lupus anticoagulants. More recently, the laboratory investigation has been expanded by including activated protein C (APC) resistance, due or not to the presence of the factor V Leiden mutation; hyperprothrombinemia, due to the presence of the prothrombin mutation G20210A and hyperhomocysteinemia, due to impairment of the relevant metabolic pathway because of enzymatic and/or vitamin deficiency. Testing for thrombophilia may be useful for many reasons. First, the results of testing may provide valuable information to assess the risk of recurrence in the proband. Second, testing family members is useful for prophylactic and diagnostic purposes. Third, the identification of patients bearing combined defect helps to identify those at increased risk for thrombosis. Testing is recommended for patients with a past history of thrombosis and should be extended to their first-degree family members. Since most of the tests are not reliable during anticoagulation, it is preferable to postpone laboratory testing until after discontinuation of the treatment. Whenever possible testing should be performed by means of functional assays. DNA analysis is required for the prothrombin mutation G20210A. Laboratory diagnosis for antiphospholipid antibodies/lupus anticoagulant should be performed by a combination of tests including phospholipid-dependent clotting assays and solid phase anticardiolipin antibodies. Hyperhomocysteinemia may be assessed by high-pressure liquid chromatography methods, or by fluorescence polarization immunoassays.     

Autoimmunity and idiopathic dilated cardiomyopathy: where we stand?

Idiopathic dilated cardiomyopathy (DCM) with its heterogeneous phenotype and genotype remains one of the leading causes of severe heart failure particularly in the younger. Even in the elderly, it appears around 15% of heart failure is due to DCM. Despite great improvements in heart failure therapy, prognoses remains poor. One of the most important reasons is that the present heart failure management is aimed mostly at restoration of neurohormonal balance, rather than targeting primary causes of the disease. As a matter of fact, a substantial subgroup of DCM and chronic heart failure is accompanied by autoimmune mechanism, in particular a wide spectrum of autoantibodies. For almost two decades, the autoimmune hypothesis has been considered a "fairy tale". Today, we have better understanding of autoimmune mechanism in DCM. This focused issue is aimed to summarize what has happened in the last two decades in the context of basic understanding of underlying mechanisms and clinical relevance.     

Supramolecular assemblies in functional siRNA delivery: where do we stand?

The discovery of RNA interference (RNAi) has excited the scientific field due to its potential for wide range of therapeutic applications. The pharmacological mediator of RNAi, short interfering RNA (siRNA), however, has faced significant obstacles in reaching its target site and effectively exerting its silencing activity. Effective pharmacological use of siRNA requires ‘carriers’ that can deliver the siRNA to its intended site of action. The carriers assemble the siRNA into supramolecular complexes that display functional properties during the delivery process. This review will summarize non-viral approaches to siRNA delivery, emphasizing the current obstacles to delivery and the mechanisms employed to overcome these obstacles. The carriers successfully pursued in pre-clinical (animal) models will be presented so as to provide a glimpse of possible candidates for clinical testing. Supramolecular assembly of nucleic acids with carriers will be probed from thermodynamics and computational perspectives to understand supramolecular structures and their dynamics. The delivery and trafficking requirements for siRNA are then dissected and engineering approaches to overcoming these barriers will be articulated. The latter has been attempted both at the cellular levels, focusing on intracellular barriers, as well as systemic level, emphasizing macroscopic challenges affecting siRNA delivery. Clinical experience with non-viral siRNA delivery is summarized, highlighting the nature delivery modes attempted in clinical settings. We conclude with a perspective on the future of siRNA therapeutics, specifically concentrating on the possible impact of non-viral carriers in the field.     

Molecular cytogenetics of lymphoma: where do we stand in 2010?

For the past 20 years most malignant lymphomas have been classified as clinicopathological entities, each with its own combination of clinical, morphological, immunophenotypic and molecular genetic characteristics. Molecular and cytogenetic abnormalities can be detected by a wide range of techniques, ranging from conventional karyotyping to single nucleotide polymorphism analysis. In this review, we consider the common genetic abnormalities found in lymphoma and discuss the advantages and disadvantages of individual techniques used in their detection. Finally, we discuss briefly possible novel developments in the field of lymphoma diagnostics.     

Standardization of allergen extracts for immunotherapy: where do we stand?

PURPOSE OF REVIEW: The current state of the art in allergen standardization and recent progress in the field is summarized, and future developments are discussed. RECENT FINDINGS: The main focus of recent research in allergen standardization was on sandwich enzyme-linked immunosorbent assays or competitive tests for the quantification of individual allergens in extracts. New assays for quantifying major or minor allergens have been developed for tree and weed pollens from the Mediterranean area, grass pollens, and foods such as peanut and apple. In several cases, a good correlation with allergenic activity, measured by inhibition tests, was obtained. In addition, the potential of cellular mediator release assays in allergen standardization was evaluated in one study. SUMMARY: Several new tests have been developed to make more major and minor allergens from various allergen sources accessible to allergen standardization programmes such as the CREATE project. It is expected that assays to determine the majority of all clinically relevant major allergens from aeroallergen sources will be available in the near future. Standardized and validated mediator release assays may be a complementary tool for evaluating the biological potency of reference allergens and for correlating allergen concentrations to biological potency.     

Subcutaneous and sublingual immunotherapy:Where do we stand?

Though symptoms of allergic diseases can be reduced by the use of drugs such as corticosteroids,antihistamines or leukotrien antagonists,the only treatment directed to change the natural course of allergic disease is allergen-specific immunotherapy(SIT). Its efficacy can last years after the cessassion of the treatment.SIT brings on regulatory T cells with the capacity to generate interleukin-10 and transforming growth factor-b,restricts activation of mast cells and basophils,and shifts antibody isotype from Ig E to the noninflammatory type immunoglobulin G4. Subcutaneous(SCIT)and sublingual(SLIT) immunotherapy are the two most used ways at the present for applying SIT. These two treatments were demonstrated to be effective on reducing symptoms and medication use,in prevention of new sensitizations and in protecting from progression of rhinitis to asthma. The safety of SLIT appears to be better than SCIT although there have been a few head to head comparisons. In order to overcome compliance problems or possible systemic side effects which maybe faced during this long-term treatment,recent investigations have been focused on the implementation of allergens in quite efficacious and safer ways.