Preventive and personalised medicine: Where are we now?
Tatjana Josifova1, Olga Golubnitschaja2
1Universtity Hospital Basel, Eye Clinic, Vitreoretinal Department, Switzerland
2Reinische Friedrich-Wilchelms-University of Bonn, Department of Radiology, Germany
Diabetes mellitus (DM) is a progressive disease with high morbidity and mortality. There is a cascade of different changes as a result of a group of metabolic disorders, characterized by impaired glucose metabolism, and consequent hyperglycemia complications. Dysregulation of glucose/insulin homeostasis leads to increased production of Reactive Oxygen/Nitrogen Species and consequent damage to chromosomal/mitochondrial DNA. Long term accumulation of DNA mutations is a triggering factor for the increased risk of cancer in diabetic patients. High risk for infectious disorders and induced viral proto-oncogenic activity may further contribute to cancer provocation. Increased oxidative stress has been implicated in molecular pathomechanisms in diabetic patients and can affect the signalling pathways of vasoinhibins which are some of predictive factors for high risk conditions in DM. One the most difficult complications are eye changes presented in the form of DR (diabetic retinopathy) and DM (diabetic maculopathy). DR is the primary cause of irreversible blindness and visual impairment in working-age adults.
Among other risk factors, chronic hyperglicemia should be emphasized which, by producing reactive oxygen species, activates multiple biochemical pathways that lead to retinal microvascular dysfunction. An early event of vascular damage is the loss of pericytes and endothelial cells resulting in acellular and ischemic capillaries. Over time, intraretinal hemorrhages and capillary occlusion create areas of ischemia, and the resulting hypoxia induces the production of proangiogenic factors, such as vascular endothelial growth factor (VEGF).
The prevalence of proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME) is closely related to the duration of diabetes. During a life-time more than 50% of patients with type 2 diabetes develop visual loss, versus 1/3 of patients with type 1 diabetes. The initial therapeutic approaches in the treatment of PDR is surgical. Laser photocoagulation (LFK) - retinal burns is still the “gold standard” in prevention and treatment of PDR. Grid laser photocoagulation, intravitreal anti-VEGF drugs and surgical treatment of the vitreoretinal tractions, is up-to date cure of DME. High risk patients for severe visual loss development type 1 DM - 26%, compared to 36% in type 2 diabetic patients, have never had their eyes examined. Recent investigations show that 32% of patients with diabetes at high risk for visual loss never undergo an eye examination. Results of the examination, have showed eye complications among the investigated group such as: DR (61%), cataract, glaucoma or another ocular manifestations.
In order to prevent the occurence of the impaired risk factors and diabetic complications, health care and eye care delivery system at a personal-based level should be enhanced in every society. Focusing on the “person”, and not on the “patient” and using new investigation techniques at a basic level while searching the high risk population is the only key to success.
Key words: preventive medicine; individualized medicine; diabetes mellitus; diabetic retinopathy
How to predict cancer?
Department of Biotechnology, University of Rijeka, Rijeka, Croatia
European Medical Research Council, European Science Foundation, Strasbourg, France
Almost all diseases have a genetic component: we are born with a genome that imbues us with a certain risk of disease. The earlier we can detect and quantify this risk, the earlier we can intervene. Rapid developments in biomedical research can thus enable a revolution in health care. It turns out, however, that knowing a gene’s sequence by itself is only of partial use to inform on a specific disease risk or explain heterogenic responses to treatment. Except in a few particular monogenic diseases, one gene alone is not the ultimate predictor. What is often more pertinent to know is, it appears, which proteins and other key molecules are actually present in specialized groups of cells. These characteristics are termed the ‘cellular phenotype’, the actual observable traits of an organism.
Hence, an important goal in personalized medicine involves identifying the traits that a cell actually exhibits in terms of quantifiable alterations in the expression of molecules such as proteins, different RNA forms, carbohydrates, lipids and other metabolites. In this regard, proteomic, transcriptomic, glycomic, lipidomic and metabolomic profiling provides a picture of the cell that is much closer to the disease than genetic profiling alone. Finally, an additional level of complexity that has emerged as a result of genome-wide analysis and insight from molecular studies on gene regulation is the epigenome. While two people might have identical gene sequences at a particular point on their genome, the way that their individual DNA is packaged into chromatin at that point can have a profound effect on the activation of that gene and, as a consequence, its involvement in a pathophysiological pathway that leads to disease. In order to facilitate the implementation of personalized medicine into healthcare and thereby fully benefit at the societal level from the potential significant contributions made by this novel area to modern medicine, integration needs to be well prepared and based on thorough strategic analysis.
We at European Medical Research Council, European Science Foundation have taken initiative to launch a strategic analysis of the emerging field of personalized medicine. This analysis would involve the following general areas: emerging technologies, data management and analysis, implementation into the clinic, economic and legal aspects, and social and societal impacts of personalized medicine. The challenges ahead are significant, and it is becoming clear that regulatory systems operate in a far more complex ways than we might have previously thought. Nevertheless, these technologies could lead to innovative therapies, limit adverse effects of treatments, increase the quality of clinical care, create an optimal fit between a patient and a treatment, and decrease the costs of healthcare. The author will discuss possibilities how to predict cancer from the – omics point of view.
Key words: individualized medicine; genetic testing; early detection of cancer
National programs of preventive medicine in Croatia
Dr. Andrija Stampar Institute of Public Health, Zagreb, Croatia
Introduction: A significant increase in the incidence and mortality of breast cancer (BC) and colorectal cancer (CRC) has been detected during the last twenty years. Despite the progress in medical practice and science there has been no indicative change in the 5-year survival of patients. There is clear evidence that screening can reduce BC and CRC mortality and improve outcomes. In almost all developed EU countries screening programs are organized.
Methods: Croatian National programs for BC and CRC screening were established by Ministry of Health and Social Welfare since the end of 2006 (BC) and the end of 2007 (CRC). The network of coordinators in each county institute of public health is obliged to ensure implementation of Programs: for BC screening sending invitation for mammography; for CRC performing of fecal occult blood testing (FOBT), followed by colonoscopy in all positive cases.
Results: At the first round of BC screening 720,982 women were summoned for mammography. The overall compliance was 63%, or, however, even greater than 80% in some counties. There were 1586 cancers detected (4.8/1000 mammograms). Of the 203,846 individuals screened until the end of year 2010 with FOBT, 12,523 (7.1%) were found to be positive. Colonoscopy was performed in 7,809 cases (compliance 74.7%). Screening has identified 451 CRC patients; 5.9% of FOBT-positive patients and 0.22% of all screened individuals proved to have CRC.
Discussion/Conclusion: These preliminary results suggest a need of further strengthening of Croatian National programs for BC and CRC screening.
Key words: screening; breast cancer; colorectal cancer
Programs of predictive medicine in Europe
Vita-Salute San Raffael eUniversity, San Raffaele ScientificInstitute, Genomic Unitforthe Diagnosiso fHuman Pathologies, Centre forTranslational Genomics and Bioinformatics, and Diagnosticae Ricerca San Raffaele SpA, Milan, Italy
The completion of human genome project and the development of new technologies for DNA testing started the revolution of the diagnostic laboratory. Every day, researchers discover the functions of new genes and increase the knowledge that can be translated into clinical practice. This growth in knowledge fuels, in turn, the expansion of DNA testing both for diagnosis and prediction of disease susceptibility. Moreover in the post genomic era, the screening of many different genetic polymorphisms and copy number variations in large populations represents a major goal that will facilitate the understanding of individual genetic variability in the development of multi-factorial diseases and drug response and toxicities.
For the future of genomics is demanding the rapid evolution of miniaturization and high-throughput genotyping technologies toward increased speed and reduced cost.
The use of personal genetic information to predict disease susceptibility and guide proactive care has the power to transform our entire healthcare system. In the future, knowing one’s genetic code will allow a person to make lifestyle and environmental changes at an early age to avoid or lessen the severity of a genetic disease. Advance knowledge of susceptibility will allow for careful monitoring and early intervention. Knowledge of a patient’s genetic profile will allow a doctor to prescribe the most effective medication with least amount of side effects. The profile will also show how well the body metabolizes allowing doctors to determine the safest and most effective dosage. Prescribing drugs with little or no side effects will increase patient compliance. Key research challenges may be addressed at the EU level,for the development of the Common Strategic Framework (CSF) which will govern EU research and Innovation funding from 2014.
Key words: human genome project; new technologies; multi-factorial diseases; pharmacogenetics; predictive medicine
The role of laboratory medicine in predictive medicine
Department of Laboratory Diagnostics, School of Medicine, University of Zagreb, University Hospital Center Zagreb, Zagreb, Croatia
Predictive medicine is a new area of health care that involves the possibility to prevent a disease before it affects individuals, and thus encourages them to change their lifestyle. This area also introduces a novel aspect of medical practice and accompanying new relations between physicians, laboratory experts and patients.
The application of predictive medicine comprises the following fields: reproductive medicine and pediatrics, neurodegenerative diseases, diabetes, molecular oncology, infectious diseases, epigenetics and ageing, and pharmacogenetics; it involves the prediction of risk for illnesses like, e.g., breast cancer and molecular diseases.
Similarly to preventive and personalized medicine, predictive medicine does not focus on diagnosis or therapy of existing disease, but rather on risk detection and reduction, and it is therefore considered that it will play one of the leading roles in the medicine of the 21st century. The development of new technologies in laboratory medicine has influenced the development of prospective health care. Thus, cytomics, genomics, proteomics, metabolomics and bioinformatics impact on the prediction of disease risk, determination of disease load, pathogenesis definition, anticipation of disease-related events, and therapeutic evaluation.
Within the framework of personalized medicine, the proper application of predictive medicine, that includes the use of early biomarkers, results in advantages for the patient in terms of prevention and early disease detection and in advantages for the healthcare system that involve possible reduction in healthcare costs.
Current progress in laboratory medicine, including molecular and genomic testing, allows measurements at the level of nucleic acids, proteins and metabolites and thus contributes to diagnosis and therapeutic monitoring within the framework of personalized medicine.
Key words: laboratory medicine; predictive medicine; personalized medicine
Predictive diagnosis of prostate cancer and colon cancer
Institute for Clinical Chemistry, Medical Faculty Mannheim of the University of Heidelberg, University Hospital Mannheim, Mannheim, Germany
Prostate cancer is the most prevalent malignant disease in men. Early diagnosis is the major goal of screening program. However, the high prevalence of localized PCa, the difficult classification of this malignancy and the low positive predictive values of diagnostic tests generate the serious problem of overdiagnosis. Great efforts are being made to improve this situation by identifying novel biomarkers for a better prediction of clinically relevant cases.
A somewhat different situation exists in colorectal cancer, because screening by colonoscopy is effective and tumour classification can be regarded as solved by means of molecular profiling.
Furthermore, specific targeted therapies exist or are being explored that – on the basis of scientific pathobiochemical evidence – promise higher effectiveness. Recent developments and analytical technologies allowing to earlier diagnosis and improved monitoring of recurrent and progressive disease will be discussed for these two cancer entities.
Key words: prostate cancer; colorectal cancer; screening; individualized medicine
Predictive diagnosis of breast cancer
Laboratory for Hereditary Cancer, Division of Molecular Medicine, Rudjer Boskovic Institute, Zagreb, Croatia
Breast cancer is one of the most frequent tumors in women. Epidemiological data indicate that 5-15% of all breast and/or ovarian cancers are inherited, also is known that mutations in BRCA1 and BRCA2 genes play a major role in the hereditary susceptibility for this disease. Women carrying a mutation in BRCA1 or BRCA2 gene have a 45-85% risk of developing breast cancer, and 11-39% risk of developing ovarian cancer, until the age of 70.
Tumors in mutation carriers contain nonfunctional BRCA1 or BRCA2 genes, which are involved in DNA repair in healthy cells. These tumors show and increased sensitivity to DNA damaging chemical agents and to PARP1 inhibitors. New targeted therapies of this type are already in use for treatment of mutation carriers. Successful treatment is most likely to be achieved through cooperation of a pathologist, oncologist and a genetic laboratory performing BRCA genes mutation screening.
In Croatia, an average of 2,200 new breast and 400 ovarian cancer cases have been reported annually over the last ten years (with a moderate tendency of increase), and 800 women die of breast cancer each year (Central Bureau of Statistics of Republic of Croatia and Croatian National Institute of Public Health, 2006).
The recent testing of inherited predisposition to breast and ovarian cancer in Croatia based on status of BRCA1 and BRCA2 (our own protocols certified by EMQN) in Croatia (funded by The Terry Fox Foundation and supported by Croatian League Against Cancer) showed mutation frequency in the region.
Key words: hereditary breast cancer; BRCA1; BRCA2; PARP inhibitors; individualized medicine
Predicting success of the treatment of oncologic diseases: can pharmacogenetics help?
Polyclinic Analiza Lab, Zagreb, Croatia
Chairperson of Croatian Society of Medical Biochemists
Chairperson of EFCC Committee of Education and Training
The aim of predictive medicine is to predict future disease of an individual and thus allow both physicians and patients to be proactive in transforming their life habits and in heightened monitoring of their lifestyle in order to prevent or delay the occurrence of disease.
Pharmacogenetics has similar aim that is based on the fact that therapy success can be predicted by determining the genotype of an individual. Pharmacogenetics studies the molecular mechanisms included in therapeutic response with the aim to achieve treatment optimization that combines optimal drug efficiency and the minimal risk of side effects.
Cancer chemotherapy is mostly determined empirically and most cytotoxic substances are administered in fixed doses determined on the basis of body surface area or body weight of an individual. Most of these drugs have a narrow therapeutic index and serious consequences in case of too low dose or overdosage. Approximately 7% of patients demonstrate serious side effects as a result of antitumor therapy.
Pharmacogenetics studies genetic variations, or gene polymorphisms, that code for specific drug metabolizing enzymes and that can be phenotypically characterized as slow, fast or even ultra fast metabolizers. Gene polymorphisms in target molecules or drug receptors may lead to excessive or too low expression of target molecules or drug receptors, which may lead to resistance or toxicity of standard chemotherapeutic cycles.
Genotyping tests are currently available that may be used to predict the metabolic status of an individual and thus allow assessment of the risk for drug inefficiency or toxicity. Clinical application of pharmacogenetics involves patient therapy with thiopurines, fluorouracil and irinotecan, which results in significant improvement in patient treatment. In the future, the clinical validation of an increasing number of pharmacogenetic tests and the development of new highly efficient genotyping technologies should further promote pharmacogenetics in clinical practice based on its predictive role in treatment where a drug is “tailored” according to patient’s needs.
Key words: pharmacogenetics; antitumor drugs; drug metabolizing enzymes; predictive medicine; therapy optimization
Pharmacogenetic approach in prediction of the anticoagulation therapy success
Department of Laboratory Diagnostics, School of Medicine, University of Zagreb, University Hospital Center Zagreb, Zagreb, Croatia
Dosing of the coumarin type anticoagulants presents a challenging task due to their narrow therapeutic range and large variability in dose-response relationship. Warfarin is the most commonly prescribed oral anticoagulant for long-term treatment and prevention of thromboembolic events. The patient’s response to warfarin and dose requirements are influenced by, besides a number of factors, pharmacogenetic variations such as single nucleotide polymorphisms in the gene encoding the cytochrome P-450 2C9 enzyme (CYP2C9). An association between possession of at least one CYP2C9*2 or CYP2C9*3 allele and reduced warfarin dose requirement, severe overanticoagulation, major bleeding risk, and delayed time to reach stabilization has been convincingly demonstrated. Recent studies indicate that the single nucleotide polymorphisms in the gene encoding the vitamin K epoxide reductase (VKORC 1) contribute even to a larger extent to variability in response to warfarin. Although most of the patients with elevated INR are successfully managed in outpatient clinics, major or minor hemorrhagic complications are the reasons for referral to emergency department and urgent reversal of anticoagulation or hospitalization. Excessive anticoagulation during long-term therapy could be due to appearance of triggering factors, such as the progression of cancer, infection, or heart failure.
Malignant diseases are associated with abnormalities of coagulation, and are known to cause thrombophilic state and often results in the need for long-term oral anticoagulation therapy, but it is clearly demonstrated the relationship between malignancy and warfarin-induced coagulopathy in a number of settings. Possible mechanisms include a direct effect on coagulation proteins production or function, treatment-related hepatic effects, malnutrition or a potentiating interaction with warfarin. Many studies confirmed that genotyping (VKORC1 and CYP2C9 variants as important genetic markers) could provide the valuable aid in the management of warfarin therapy, particularly in patients with multiple risk factors for hyperanticoagulation associated hemorrhagic complications.
Key words: coumarins; anticoagulants; pharmacogenetics; individualized medicine
Dignity of human being and ethycal relativism
Department of Internal Medicine, School of Medicine, University of Zagreb, University Hospital Centre Sestre milosrdnice, Zagreb, Croatia
Today, at the begining of the 21st century we a are faced with dominant paradigm of our civilization based on subjective relativism. “Modern society” strongly promotes rational liberalism and Cartesianic phylosophy, included the illusion of unlimited possibillty in science investigations. Considering Hipocratic oat, UNESCO ethical declarations, religious, cultural and biopolitical features of the society, as well as scientific practice created by the cost/benefit dynamics and language engineering, bioethical principles in scientific achievements and everyday medical practice are necessary in order to promote institutional contacts on educational progams about main topics in bioethics (genetics, nanotechnology, stem cell research, abortion, euthanasia, medically assisted reproduction, cloning of human beings, etc). In perspective, it is of great importance to promote authentic life ideals, with the aim of asserting human dignity in every moment of our lives in every day medical practice, education and science.
Key words: dignity of human being; ethycal relativism; medical ethics