Biomarkers of the immunomodulatory effect of immunosuppressive drugs in transplant recipients

Nowadays, monitoring of the immunosuppressive therapy received by solid organ transplant recipients is based on measuring drug blood levels to achieve concentrations within the established therapeutic range. This strategy largely prevents the toxicity associated with this kind of treatment but is insufficient to determine the individual response in each patient or to tailor the dose to each patient's real requirements. In the field of solid organ transplantation, new approaches able to reflect the individual responses produced in each patient are required to monitor immunosuppressive therapy and to improve the efficacy and safety of treatment. Thus, in the last few years, preliminary studies evaluating new specific biomarkers of the biologic effect of immunosuppressive drugs (pharmacodynamic monitoring) have been carried out. The results of these pilot studies show the potential of monitoring of these specific biomarkers to improve the safety and efficacy of immunosuppression, although the complexity of these analyses and the lack of standardized methodologies currently limit the routine application of this technique. Based on the previous studies performed to date on biomarkers, which included a small number of patients, no conclusions can be drawn as to which are the most appropriate biomarkers to prevent organ rejection or adverse events. Consequently, these biomarkers need to be validated in multicenter clinical trials.The present article reviews some biomarkers that have been proposed to evaluate currently approved immunosuppressants, such as target enzymes, cytokines, lymphocyte activation biomarkers, and cellular immune response, as well as the most promising results in this field.     

Critical Evaluation of the Efficacy and Safety of Anticholinergics in Overactive Bladder

Antimuscarinic agents are the primary pharmacologic treatment of overactive bladder (OAB), and objective clinical data are available in a range of formats including head-to-head studies, systematic reviews and adjusted indirect comparisons. This paper reexamines the various data available on the safety and efficacy of the antimuscarinics. Clinical studies determine whether one treatment is better than another, rather than examining which treatment is best for the individual patient. Favourable treatment outcome may not be attained because of unrealistic expectations of the patient, who may also be dissatisfied with the complications of the treatment. Comparisons between clinical studies on drug therapy for OAB may be complicated by the high placebo response rates. Variations exist in the study populations in terms of symptom severity and tolerance of adverse events, and the diverse methods of assessment employed. Apart from head-to-head studies, meta-analyses can be employed to compare different classes of drugs (lumping method) or individual drugs (splitting method) by pooling of clinical data. The adjusted indirect comparison method has been developed as a method to allow the outcome of two different trials to be compared. Overall, data from clinical trials indicate that the commonly used antimuscarinics have different tolerability and safety profiles but broadly similar efficacy profiles. Consequently, therapy should be tailored to individual patient needs rather than one drug fits all.     

直肠癌术前放疗敏感性相关的分子生物学标志物

术前放疗已成为进展期直肠癌患者标准化治疗的一部分．但是患者对放疗敏感性存在差异,部分患者接受放疗后并不获益,不仅不良反应发生率增加,还需承担高昂的治疗费用。分子标志可以有效指导临床医生为患者制定最适合的治疗方案。因此．需要努力寻找有效的分子标志物以便更准确地预测放疗敏感患者。     

The molecular basis of chemoradiosensitivity in rectal cancer:implications for personalized therapies

Introduction  

Preoperative chemoradiotherapy represents the standard treatment for patients with locally advanced rectal cancer. Unfortunately, the response of individual tumors to multimodal treatment is not uniform and ranges from complete response to complete resistance. This poses a particular problem for patients with a priori resistant tumors because they may be exposed to irradiation and chemotherapy, treatment regimens that are both expensive and at times toxic, without benefit. Accordingly, there is a strong need to establish molecular biomarkers that predict the response of an individual patient’s tumor to multimodal treatment and that indicate treatment-associated toxicities prior to therapy. Such biomarkers may guide clinicians in choosing the best possible treatment for each individual patient. In addition, these biomarkers could be used to identify novel molecular targets and thereby assist in implementing novel strategies to sensitize a priori resistant tumors to multimodal treatment regimens.     

Novel biomarkers for prostate cancer: An evidence‐based review for use in clinical practice

Prostate cancer is a heterogeneous disease with disparate outcomes. Traditional clinical parameters are limited in their ability to differentiate between these cases, and there is uncertainty regarding management strategies. A number of novel biomarkers have emerged, but how best to use them at the point of care remains confusing. In the present review, we describe the most common novel biomarkers, their key supporting literature, and propose a meaningful algorithm for their use in clinical practice. To identify commercially available prostate cancer diagnostic tests, we carried out a PubMed literature search (through May 2016). Only English‐language studies were included. We restricted our search to studies published within the past 10 years in order to focus our review on novel data. Secondary sources were also examined. We identified 12 novel biomarkers and categorized them into broad areas of clinical practice: (i) early diagnosis and screening; (ii) staging and primary treatment selection; (iii) post‐treatment risk stratification; (iv) advanced disease prognosis and treatment response; and (v) emerging tests. Most validation studies rely on small retrospective cohorts and carry a high risk of bias; furthermore, most cohorts are restricted to Caucasians, with little to no representation of other geographic, racial or ethnic populations. Novel biomarkers for prostate cancer management, while potentially helpful, should not replace standard clinical information and physician judgment. They are currently best suited to serve as an adjunct to existing management tools. Clinicians should have a sound grasp of each biomarker‐based test's indications and limitations.     

Update on treatment in multiple sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. In recent years, many disease-modifying therapies (DMT) have been approved for MS treatment. For this reason, a profound knowledge of the characteristics and indications of the available compounds is required to tailor the therapeutic strategy to the individual patient characteristics. This should include the mechanism of action and pharmacokinetic of the drug, the safety and efficacy profile provided by clinical trials, as well as the understanding of possible side effects. Moreover, the evolving knowledge of the disease is paving the way to new and innovative therapeutic approaches, as well as the development of new biomarkers to monitor the therapeutic response and to guide the clinician's therapeutic choices. In this review we provide a comprehensive overview on currently approved therapies in MS and the emerging evidence-based strategies to adopt for initiating, monitoring, and eventually adapting a therapeutic regimen with DMT.     

Patient-centered management of atrial fibrillation: applying evidence-based care to the individual patient

Atrial fibrillation is the most common arrhythmia encountered in clinical practice, and it is one of the most common cardiac conditions requiring hospitalization of a patient. Several national organizations have developed guidelines for the management of atrial fibrillation. These guidelines were updated in 2011 to incorporate new advances in antiarrhythmic drug therapy and anticoagulant therapy, as well as progress in the field of catheter ablation. Many decisions about patient care involve consideration of issues related to lifestyle and quality of life rather than survival. These decisions also involve addressing the key topics of heart rate control, heart rhythm control, and stroke prevention. During the past decade, important advances in the management of atrial fibrillation have created a number of treatment options that have roughly equivalent therapeutic efficacies when they are used for several common clinical situations encountered in clinical practice. The range of available treatments for patients with atrial fibrillation provides an important opportunity for the physician to deliver patient-centered care, which uses patient values to determine the best course of treatment.     

Challenges of cancer biomarker profiling

OBJECTIVES: New biomarkers are being developed to identify individuals at risk for cancer, detect disease earlier, determine prognosis, detect recurrence, predict response to particular agents, and monitor response to treatment. This article attempts to address some of the challenges facing the research and medical communities in the delivery of new biomarkers for individualized medicine. METHODS: A variety of issues and barriers can affect the transfer of clinical tests from research to clinical practice. Differences in sample collection, handling or storage, and profiling techniques may influence the protein profile obtained by any method. RESULTS: Standard procedures and quality check schemes are necessary because there is a lack of definition to guarantee reproducibility of new procedures. From technical and economic viewpoints, the assay has to be sufficiently robust to be completed in community-based hospitals. Although traditionally cancer patients were treated with drugs of low toxicity or of high tolerance regardless of their efficacy in a given patient if the benefits of that drug are proven in both experimental and clinical conditions, recent advances have provided opportunities to adapt "tailored" treatment modalities. The evolving trend is the usage of patterns of markers instead of a single marker. Further challenges in biomarker development are in finding the relevant markers that have the right degree of specificity and sensitivity and a reliable test to measure the outcome. CONCLUSIONS: Discovery, testing, and validation of clinically appropriate and commercially useful tumor markers should permit individualization of therapy.     

Proteomics in cardiovascular surgery

Proteomics describes, analogous to the term genomics, the study of the complete set of proteins present in a cell, organ, or organism at a given time. The genome tells us what could theoretically happen, whereas the proteome tells us what does happen. Therefore, a genomic-centered view of biologic processes is incomplete and does not describe what happens at the protein level. Proteomics is a relatively new methodology and is rapidly changing because of extensive advances in the underlying techniques. The core technologies of proteomics are 2-dimensional gel electrophoresis, liquid chromatography, and mass spectrometry. Proteomic approaches might help to close the gap between traditional pathophysiologic and more recent genomic studies, assisting our basic understanding of cardiovascular disease. The application of proteomics in cardiovascular medicine holds great promise. The analysis of tissue and plasma/serum specimens has the potential to provide unique information on the patient. Proteomics might therefore influence daily clinical practice, providing tools for diagnosis, defining the disease state, assessing of individual risk profiles, examining and/or screening of healthy relatives of patients, monitoring the course of the disease, determining the outcome, and setting up individual therapeutic strategies. Currently available clinical applications of proteomics are limited and focus mainly on cardiovascular biomarkers of chronic heart failure and myocardial ischemia. Larger clinical studies are required to test whether proteomics may have promising applications for clinical medicine. Cardiovascular surgeons should be aware of this increasingly pertinent and challenging field of science.     

Evidence-Based Practice Should Supersede Evidence-Based Medicine Through Consideration of Clinical Experience and Patient Characteristics in Addition to the Published Literature

On the surface, the benefits of evidence-based medicine (EBM) seem self-evident. However, reliance on the scientific literature alone has limitations. Studies may be biased, statistically fragile, and/or not reproducible. Reliance solely on EBM may ignore physician clinical experience and individual patient characteristics and input. Reliance solely on EBM may overvalue quantitative, statistical significance, resulting in a false sense of certainty. Reliance solely on EBM may fail to consider lack of generalizability of published studies to individually unique patients. The concept of evidence-based practice goes beyond EBM and incorporates (1) EBM, (2) clinical expertise, and (3) individual patient characteristics, values, and preferences. Even if branded as evidence-based, a suggested treatment may not be the best treatment. Evidence-based practice must be considered before determining what is best for our patients.     

Pharmacogenetics of Osteoporosis: Future Perspectives

Drug response is known to be highly variable among treated patients and affected by many factors, such as age, sex, ethnicity, concomitant diseases, and pharmacological therapy. However, sequence variants in the human genome are now considered an important cause of differences in drug responses. Pharmacogenetics, which is the utilization of individual genetic data to predict the outcome of drug treatment with respect to both beneficial and adverse effects, represents an emerging field of genetics with the potential to become useful for the identification of the most effective drug and the most beneficial dose for a given individual. On the basis of these considerations and thanks to recent advances in genetics and molecular biology, pharmacogenetics is becoming a flowering field in both basic and clinical research. Nevertheless, to date the opportunity to apply pharmacogenetic approaches to drug response and the possibility to use genetic screenings to tailor decisions about pharmacological treatments have limited applications. And this is even truer in the field of osteoporosis, in which pharmacogenetic studies are in their infancy. In this paper we review the most recent data on pharmacogenetics of osteoporosis, highlighting the presentations at the Second International Meeting on Pharmacogenetics of Osteoarticular Disorders held in Florence in April 2008.     

Roux-en-Y gastric bypass is the operation of choice for bariatric surgery

Conclusion The choice of surgical procedures for an individual patient must be made by a surgeon who has all of the tools available to them in their environment. Decisions need to be made depending on the individual clinical scenario. No single tool or procedure can be considered appropriate for all patients. Assimilation of the known data is necessary for the surgeon to offer the appropriate procedure to the appropriate patient. The well-informed and well-trained individual will recognize that the best choice for most patients seeking surgical treatment for clinical severe obesity is laparoscopic RGB.     

Contribution of molecular biology to the diagnosis and therapy of colorectal carcinoma--the present and future

Colorectal cancer is one of the most frequent malignant disease and despite of the development of modern surgical and oncological treatment, it is still a very severe diagnosis for the patient. The survival of the patient after the radical surgery is mostly affected by the time of detection of the disease and by the selection of the appropriate oncological treatment. The effectivity of the oncological treatment depends mainly on the features of the malignant tissue. During the last decade, the importance of the molecular biology and it's methodology have been growing for both detection of the disease and the selection of the best treatment for the individual patient. Genetic and epigenetic characteristics of the tumours helps to predict the prognosis of the disease and also select the best treatment, which extends the disease-free and overall survival of the patient. The presented review describes the most important molecular-biological characteristics with the prognostic or predictive function, which are used in the clinical practice or are in the later phase of clinical study.     

Non-responders to phosphodiesterase type 5 inhibitors: is there a second chance?

Phosphodiesterase type 5 (PDE5) inhibitors are, today, the first treatment option for erectile dysfunction (ED). However, efficacy does not exceed 70%, while the drop-out rate is high. Therefore, salvage strategies and second/third line treatment options are necessary to restore erectile response in such patients. This literature review of the currently available data on non-responders to PDE5 inhibitors aims to discuss key issues that physicians address in everyday clinical practice. These issues include the definition of treatment failure, the identification of factors that affect treatment outcome and the management strategy for non-responders to PDE5 inhibitors. Medication, clinical and patient/partner related issues have been identified as factors related to treatment failure. Treatment outcome assessment is based not only on quality of erectile response, but also on side effect profiles and patient satisfaction. Proper instructions for PDE5 inhibitor administration and psychosexual counselling may convert a substantial number of non-responders to responders. Inappropriate use of PDE5 inhibitors is a major issue in clinical practice. Non-responders may be converted to responders after careful assessment of the proper use of a PDE5 inhibitor. Treatment options for true non-responders are under investigation and include chronic administration of PDE5 inhibitors (everyday, low dose use), switchover from one drug to another or combination treatments. Management strategies must identify patient and partner needs and expectations and involve them in the decision-making.     

Commentary: the role of cytologic analysis of voided urine in the work-up of asymptomatic microhematuria

The clinical problem of bladder cancer is its high recurrence and progression, and that the most sensitive and specific means of monitoring is cystoscopy, which is invasive and has poor patient compliance. Biomarkers for recurrence and progression could make a great contribution, but in spite of decades of research, no biomarkers are commercially available with the requisite sensitivity and specificity. In the post-genomic age, the means to search the entire genome for biomarkers has become available, but the conventional approaches to biomarker discovery are entirely inadequate to yield results with the new technology. Finding clinically useful biomarker panels with sensitivity and specificity equal to that of cystoscopy is a problem of systems biology.     

Metformin Pharmacogenomics: Current Status and Future Directions

The incidence of type 2 diabetes (T2D) and its costs to the health care system continue to rise. Despite the availability of at least 10 drug classes for the treatment of T2D, metformin remains the most widely used first-line pharmacotherapy for its treatment; however, marked interindividual variability in response and few clinical or biomarker predictors of response reduce its optimal use. As clinical care moves toward precision medicine, a variety of broad discovery-based “omics” approaches will be required. Technical innovation, decreasing sequencing cost, and routine sample storage and processing has made pharmacogenomics the most widely applied discovery-based approach to date. This opens up the opportunity to understand the genetics underlying the interindividual variation in metformin responses in order for clinicians to prescribe specific treatments to given individuals for better efficacy and safety: metformin for those predicted to respond and alternative therapies for those predicted to be nonresponders or who are at increased risk for adverse side effects. Furthermore, understanding of the genetic determinants of metformin response may lead to the identification of novel targets and development of more effective agents for diabetes treatment. The goals of this workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases were to review the state of research on metformin pharmacogenomics, discuss the scientific and clinical hurdles to furthering our knowledge of the variability in patient responses to metformin, and consider how to effectively use this increased understanding to improve patient outcomes.     

Show me the evidence

Reporting outcomes based on clinical evidence is going to set the standards for hand surgery practice. Hand surgeons will be judged by the evidence that their interventions are doing the most good for the most people at a price that patients and/or insurance companies are willing to pay. Evidence-based practice is the integration of the best research evidence with clinical expertise and patient values. The best evidence comes from randomized clinical trials, which are expensive, time consuming, and not always possible. Sometimes we have to settle for good evidence, which may be the best evidence that is available. Nevertheless, if the future demands good evidence, then as hand surgeons and researchers we need to supply that evidence. Thus, first we have to know how and where to look for what's out there and then what we can do to add to this body of knowledge.     

A primer on selected aspects of evidence-based practice relating to questions of treatment. Part 1: asking questions, finding evidence, and determining validity

SYNOPSIS: The process of evidence-based practice (EBP) guides clinicians in the integration of individual clinical expertise, patient values and expectations, and the best available evidence. Becoming proficient with this process takes time and consistent practice, but should ultimately lead to improved patient outcomes. The EBP process entails 5 steps: (1) formulating an appropriate question, (2) performing an efficient literature search, (3) critically appraising the best available evidence, (4) applying the best evidence to clinical practice, and (5) assessing outcomes of care. This first commentary in a 2-part series will review principles relating to steps 1, 2, and 3 of this 5-step model. The purpose of this commentary is to provide a perspective to assist clinicians in formulating foreground questions, searching for the best available evidence, and determining validity of results in studies of interventions for orthopaedic and sports physical therapy.