01:00 pm

Registration

01:15 pm – 02:30 pm

VEGF Consortium

closed meeting

02:30 pm – 03:30 pm

The MAST4HEALTH Consortium, GUTENBERG and beyond

closed meeting

03:30 pm – 04:30 pm

1st dedicated poster session

04:30 pm – 05:00 pm

WELCOME

Sofia SIEST, Nancy, France

05:00 pm – 06:30 pm

KEYNOTE ROUND TABLE

PGx ANALYSIS IN THE MEDICAL DIAGNOSTIC LABORATORY – FROM SCIENCE TO CLINICAL DECISION SUPPORT (CDS)

Chairs: Raute Sunder-Plassmann, Vienna, Austria / Markus Paulmichl, Salzburg, Austria

Supported by


Topics

Current PGx research

Munir Pirmohamed, Liverpool, United Kingdom

Current PGx research

Munir Pirmohamed,
Wolfson Centre for Personalised Medicine, University of Liverpool, Liverpool, UK

Although pharmacogenetics/pharmacogenomics has been around for a long time, since the completion of the human genome project, there has been a massive increase in the numbers of publications listed on PubMed every year.  Our ability to interrogate the whole genome provides us with unparalleled opportunities to identify new genetic predisposing factors in an unbiased manner for both efficacy and safety phenotypes, often leading to new insights into gene function.  Although the majority of papers are still adopting a candidate gene approach, there has been an increase in genome-wide approaches, using both SNP genotyping arrays and sequencing (exome/whole genome) techniques.  The latter is also identifying rare variants, and the overall contribution of rare variants to pharmacogenomic phenotypes needs more study.  The availability of large-scale biobanks such as the UK biobank also provides an opportunity to identify novel pharmacogenomic phenotypes, but may be limited by the depth of clinical phenotypes available within the biobanks, but partially compensated for by the large sample size.  The issue of diversity in pharmacogenomics research is important, and further work in different ethnic groups is important in order to ensure that we do not exacerbate race and health inequalities.  Over the last 5 years, there has also been an increasing drive towards implementation of pharmacogenomics into clinical care.  This has largely been driven in selected centres by champions, with good results, but further efforts at implementation throughout entire healthcare systems is needed.

Pre-emptive PGx

Ron van Schaik, Rotterdam, The Netherlands

Pre-emptive PGx

Ron HN van Schaik,
Professor of Pharmacogenetics, Dept. Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands

Currently, there is an increase in pharmacogenetic testing in routine care. Especially for the DPYD (5-FU/capecitabine), CYP2D6 (antidepressants) and CYP2C19 (clopidogrel)  tests, we see more requests in our laboratory. Meanwhile, we do see a patient driven demand to have more genes tested at the same time when they have to send in a sample for PGx tested. Also economically, there is an advantage to perform multiple gene testing, which brings the issue of timing. Instead of waiting until a PGx test is needed, pre-emptive genotyping will ensure that the appropriate genetic information to guide drug therapy is already available. This will maximize the effect of PGx while minimizing the costs. The question now is: when are we ready for implementing pre-emptive PGx testing?

Future development of pharmacogenomics as a clinical tool

Magnus Ingelman-Sundberg, Stockholm, Sweden

Future development of pharmacogenomics as a clinical tool

Magnus Ingelman-Sundberg
Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, Stockholm, Sweden

Pharmacogenomic biomarkers for prediction of drug metabolism, toxicity and response are currently approved by FDA and EMA and are to some extent implemented into clinical work. These mainly identify common genetic variations in genes encoding enzymes, transporters and targets. However, the interindividual variation in e.g. drug metabolism between individuals having the same phenotype based on genotype is huge and the resolution of pre-emptive genotype- dependent prediction for the individual patient not sufficient. In the talk emphasis will be given to, in addition to commonly considered alleles, also include i) novel haplotypes within each defined genotype, ii) contribution of genetic variants outside the locus encoding the enzyme/transporter and iii) the role of rare mutations. Implementing NGS and algorithms able to predict the functionality of missense mutations in the pharmacogenes and a broader aspect for the identification of variants affecting drug response would improve currently used pharmacogenomic models providing a further step towards a real personalized drug treatment.

PGx reports

Raute Sunder-Plassmann, Vienna, Austria

PGx reports

Raute Sunder-Plassmann
Klinisches Institut für Labormedizin, Genetisches Labor, Vienne, AUSTRIA

Preemptive PGx diagnostics is still not very common and active PGx clinical decision supports systems (CDSS) are rare. Thus, in daily clinical practice, physicians – usually in the setting of hospitals or medical centers – rely on reactively ordered PGx tests to adjust or change an initiated standard therapeutic regimen, if necessary. They expect the laboratory PGx reports to be easy to understand and brief, to focus on the current medication and relevant actionable genetic variants and to provide dosing recommendations based on the patient’s anticipated response to the currently prescribed drug. Additionally, links to web-based PGx portals are highly appreciated.
A more comprehensive PGx report – beyond PGx variants relevant to the current medication – is unequivocal beneficial for patients and should be included in their electronic health record. However, in the absence of active institutional CDSS the application of these PGx data in daily clinical routine might be challenging.

Standardization in PGx diagnostics

Markus Paulmichl, Salzburg, Austria

Open Panel Discussion with the Audience

06:30 pm – 07:30 pm

KEYNOTE LECTURE

Chairs: Georges Dagher, Paris, France / Sofia Siest, Nancy, France

Advances in Cancer Detection

Nickolas Papadopoulos, Baltimore, United States 

Advances in Cancer Detection

Nickolas Papadopoulos, Ph.D
The Johns Hopkins Institutions, Oncology and Pathology, Ludwig Center for Cancer Genetics & Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Baltimore, United States

The earlier a cancer is detected the higher the chance for a successful outcome. For many cancers there are not any screening modalities available. The ability to identify cancers through blood testing is one of the most exciting advances in cancer diagnostics. In a screening setting it provides the opportunity to detect multiple cancer types with a single test. Liquid biopsy also has the potential to detect early signs of minimal residual disease and recurrence. The presentation will outline these opportunities along with challenges associated with such clinical applications. We will discuss the biomarkers, technologies and the type of studies required to develop and evaluate the utility of such tests.

07:30 pm – 09:00 pm

WELCOME RECEPTION

at the De Sol Spa Hotel

09:00 am –11:00 am

SESSION I

LIQUID BIOPSY, PAST, PRESENT, FUTURE

Chairs: Heiko Meyer, Hamburg, Germany / Georges Dagher, Paris, France

Sponsored by

09:00 am – 09:30 am

Liquid Biopsy: From Discovery to Clinical Implementation

Klaus Pantel, Hamburg, Germany

Liquid Biopsy: From Discovery to Clinical Implementation

Klaus Pantel
Institute of Tumor Biology, University Cancer Center Hamburg, University Medical Center Hamburg Eppendorf, Hamburg, Germany

The molecular analysis of circulating cell-free tumor DNA (ctDNA) and circulating tumor cells (CTCs) released into the blood can provide clinically relevant information as “liquid biopsy” (Pantel & Alix-Panabieres, Nature Rev. Clin. Oncol. 2019; Alix-Panabieres & Pantel, Cancer Discovery 2021) and provide new insights into tumor biology (Keller & Pantel, Nature Rev. Cancer 2019). CTC analyses involves label-dependent or label-independent enrichment steps, single cell identification and subsequent molecular characterization. A variety of targeted and non-targeted approaches have been used to assess ctDNA. Besides NGS-based approaches targetable genetic alterations can be also revealed using a MassARRAY-Based ctDNA assay (Belloum et al. Cells, 2020; Schneegans et al., Mol. Oncol. 2020). Liquid biopsy analyses with validated platforms provide information on early detection of cancer, identification of cancer patients at risk to develop relapse (prognosis), and it may serve to monitor tumor evolution, therapeutic targets or mechanisms of resistance on metastatic cells. Metastatic cells might have unique characteristics that can differ from the bulk of cancer cells in the primary tumor currently used for stratification of patients to systemic therapy. Repeated needle biopsies of metastatic lesions are possible but invasive and some location and difficult to access. In contrast, monitoring of blood samples in the context of therapies is only minimally invasive and can also identify tumor evolution and tumor subtype switches, which may then lead to the selection of appropriate therapies for cancer patients based on the actual molecular composition of their recurrent metastases. In conclusion, liquid biopsy analysis can be used to improve the management of individual cancer patients and contribute to personalized medicine. New promising liquid biopsy markers include extracellular vesicles, circulating microRNAs and tumor-educated platelets as well as circulating host cells (e.g., immune cells, endothelial cells or cancer-associated fibroblasts). Technical standardization and clinical validation of liquid biopsy assays are essential and currently performed by the ELBS (European Liquid Biopsy Society; www.elbs.eu) and other organisations worldwide (Connors et al., Crit. Rev. Hematol. Oncol. 2020). In particular, interventional clinical studies will provide evidence for the clinical utility of liquid biopsy in oncology.

09:30 am – 10:00 am

Metastasis-Competent circulating tumor cells in colon cancer

Catherine Alix-Panabieres, Montpellier, France

 Metastasis-Competent Circulating Tumor Cells in Colon Cancer

Catherine Alix-Panabières1,2
1Laboratory of Rare Human Circulating Cells (LCCRH), University Medical Centre of Montpellier, Montpellier, France
2CREEC/CANECEV, MIVEGEC (CREES) University of Montpellier, CNRS, IRD, Montpellier, France

The development of blood-based, tumor-specific biomarkers called real-time liquid biopsy such as circulating tumor cells (CTCs) have made significant advances over the last years in cancer research.
Real-Time Liquid Biopsy has been introduced1 as a new diagnostic concept predicated on the analysis of circulating tumour cells (CTCs) or circulating tumour-derived factors, in particular, cell-free tumour DNA (ctDNA). Highly sensitive liquid biopsy assays have been developed that can now be applied to detect and characterize (i) minimal residual disease, which reflects the presence of tumour cells disseminated from the primary lesion to distant organs in patients who lack any clinical or radiological signs of metastasis or residual tumour cells left behind after local therapy that eventually lead to local recurrence2,3; This application is the new frontier of liquid biopsy analyses, which are challenged by the very low concentrations of CTCs in blood samples; (ii) CTCs are promising new biomarkers potentially useful for prognostic prediction and (iii) monitoring of therapies in patients with solid tumors including colon cancer; (iv) CTC research opens a new avenue for understanding the biology of metastasis in cancer patients4.
However, an in-depth investigation of CTCs is hampered by the very low number of these cells, especially in the blood of colorectal cancer patients. Thus, the establishment of cell cultures and permanent cell lines from CTCs has become the most challenging task over the past year5.
We described, in 2015, the in vitro expansion of colon CTCs and established the first permanent cell line from CTCs of a metastatic colon cancer patient6. This colon CTC line designated CTC-MCC-41 is in culture for more than six years and has been characterized at the genome, transcriptome, proteome and secretome levels. This thorough analysis showed that CTC-MCC-41 cells resemble characteristics of the original tumor cells in the colon cancer patient and display a stable phenotype characterized by an intermediate epithelial/mesenchymal phenotype, stem-cell like properties and an osteomimetic signature indicating its bone marrow origin. Functional studies showed that CTC-MCC-41 cells induced rapidly in vitro endothelial cell tube formation and in vivo tumors after xenografting in immunodeficient mice. In 2017, we defined the molecular portrait of these metastasis-competent CTCs7. These results highlight that CTC-MCC-41 line display a very specific transcription program completely different than those of the primary and metastatic colon cancer cell lines. More recently, we characterized 8 additional CTC lines using blood samples from the same metastatic cancer: a unique biological material collected before and after chemotherapy and targeted therapy, and during cancer progression8. More recently, we could show that (i) the PI3K/AKT/mTOR signaling pathway plays a key role in the proliferation of the CTC-MCC-41 line9 as well as that (ii) the selective treatment pressure in colon cancer drives the molecular profile of resistant CTC clones10.
Such data may supply insights for the discovery of new biomarkers to identify the most aggressive CTC sub-populations and for the development of new drugs to inhibit metastasis-initiator CTCs in colon cancer.
Even if culturing CTCs in vitro or in vivo is not applicable to all cancer patients, it is crucial to go on with these functional studies to help the scientific and medical community to understand fully the formation of metastasis during cancer dissemination by identifying the right aggressive tumor cells to eradicate. Although, viable CTCs are not exploitable in all patients with cancer, they are a precious tool to unravel the mechanisms of metastasis formation and cancer cell dissemination through the identification/characterization of the aggressive tumor cells that need to be eradicated. The new EPIDROP technology represents an alternative for the detection of viable CTCs. It allows the enumeration and characterization of all CTCs, and gives information on their viability and functionality at the single cell level and also on their drug resistance profile in a few hours: developing an oncogram for the real-time follow-up of resistance against chemotherapy or immunotherapy is urgently needed.
We are progressing very fast in the field of liquid biopsy in cancer research. However, much effort should now focus on developing a reliable, standardized and robust method to expand CTCs from different cancer types11. To meet this challenge, projects have been started by different consortia, such as the European Liquid Biopsy Society (ELBS) program will continue. The establishment of CTC lines represents a new opportunity to decipher the metastatic cascade and, hopefully, to find ways to stop cancer dissemination. 

References

1          Pantel, K. & Alix-Panabieres, C. Circulating tumour cells in cancer patients: challenges and perspectives. Trends Mol Med 16, 398-406, doi:10.1016/j.molmed.2010.07.001 (2010).
2          Pantel, K. & Alix-Panabieres, C. Liquid biopsy and minimal residual disease – latest advances and implications for cure. Nat Rev Clin Oncol, doi:10.1038/s41571-019-0187-3 (2019).
3          Alix-Panabieres, C. & Pantel, K. Liquid Biopsy: From Discovery to Clinical Application. Cancer Discovery (2021 In Press).
4          Alix-Panabieres, C. & Pantel, K. Challenges in circulating tumour cell research. Nat Rev Cancer 14, 623-631, doi:10.1038/nrc3820 (2014).
5          Cortés-Hernández, L. E., Eslami-S, Z. & Alix-Panabières, C. Circulating Tumor Cell as the functional aspect of Liquid Biopsy to Understand the Metastatic Cascade in Solid Cancer. Molecular Aspects of Medicine (In press).
6          Cayrefourcq, L. et al. Establishment and characterization of a cell line from human circulating colon cancer cells. Cancer Res 75, 892-901, doi:10.1158/0008-5472.CAN-14-2613 (2015).
7          Alix-Panabieres, C. et al. Molecular Portrait of Metastasis-Competent Circulating Tumor Cells in Colon Cancer Reveals the Crucial Role of Genes Regulating Energy Metabolism and DNA Repair. Clin Chem 63, 700-713, doi:10.1373/clinchem.2016.263582 (2017).
8          Soler, A. et al. Autologous cell lines from circulating colon cancer cells captured from sequential liquid biopsies as model to study therapy-driven tumor changes. Scientific reports 8, 15931, doi:10.1038/s41598-018-34365-z (2018).
9          Smit, D. J. et al. High Sensitivity of Circulating Tumor Cells Derived from a Colorectal Cancer Patient for Dual Inhibition with AKT and mTOR Inhibitors. Cells 9, doi:10.3390/cells9092129 (2020).
10         Cayrefourcq, L. et al. Selective treatment pressure in colon cancer drives the molecular profile of resistant circulating tumor cell clones. Mol Cancer 20, 30, doi:10.1186/s12943-021-01326-6 (2021).
11         Alix-Panabieres, C. The future of liquid biopsy. Nature 579, S9, doi:10.1038/d41586-020-00844-5 (2020).

10:00 am – 10:30 am

Detection of clinically actionable mutations in NSCLC: is there a one-fits-all cell-free DNA test for routine clinical practice?

Ed Schuuring, Gröningen, The Netherlands

Detection of clinically actionable mutations in NSCLC: is there a one-fits-all cell-free DNA test for routine clinical practice?

P van der Leest1, TJN Hiltermann2, HJM Groen2, LC van Kempen1, Ed Schuuring1
Departments of 1Pathology and 2Pulmonary Diseases, University of Groningen, University Medical Center Groningen,  PO Box 30.001, 9700RB Groningen, The Netherlands

Background: Circulating tumor DNA (ctDNA) is a potential minimally invasive molecular tool to guide treatment decision making and disease monitoring especially when no appropriate tumor tissue biopsy is available. A suitable diagnostic-grade platform is required for the detection of tumor-specific mutations in circulating cell-free DNA (ccfDNA) with high sensitivity.
Objective: To investigate if a one-fits-all ccfDNA test exists for the different applications in the molecular diagnostics of lung cancer such as molecular profiling for treatment-decision-making, response monitoring and detection of treatment-resistant mechanisms.
Design: Determine the concordance between various ccfDNA tests using plasma collected at various time-points during therapy (at baseline before treatment initiation, at first evaluation and at disease progression) from NSCLC patients treated with tyrosine-kinase and immune checkpoint inhibitors. We evaluated the Roche Cobas® EGFR Mutation Test v2 (42 mutations in the EGFR gene), the Agena UltraSEEK® Lung Panel (74 mutations in EGFR, PIK3CA, ERBB2, BRAF, KRAS), tumor-mutation-specific Bio-Rad®-ddPCR assays and the Roche AVENIO ctDNA Expanded NGS Kit (hundreds of predictive mutations in 77 genes).
Results: Overall, the concordance to detect clinically relevant mutations in plasma comparing the different ccfDNA tests was >90% for those mutations covered by the different assays. The concordance between therapeutically targetable mutations detected in tumor tissue with NGS and in the pre-treatment plasma samples is high for all assays (~80%) and in agreement with reported data. Considerations to implement the most appropriate ccfDNA test for the different clinical applications in diagnostics of lung cancer will be discussed.
Conclusion: There is no one-fits-all ccfDNA test for all clinical application. To select the appropriate ccfDNA test for clinical questions that lead to actionable mutations, aspects like the complexity of the test, costs, reimbursement issues, turn-around-time, the number of relevant mutations covered by each assay, expertise of the diagnostic lab and availability of ccfDNA, are leading.
Acknowledgements: Several studies presented were supported by the CANCER-ID consortium (including Roche and Agena Bioscience) and unrestricted research grants of Bristol Myers Squibb, Bio-Rad, Biocartis and Agena Bioscience. Various studies were based on collaborations with MUG Graz (E Heitzer), Imagenome Montpellier (P-J Lamy) and UKE Hamburg (H Wikman).

10:30 am – 11:00 am

Donor-derived cell-free DNA testing in organ transplantation: a value proposition

Michael Oellerich, Göttingen, Germany

Donor-derived cell-free DNA testing in organ transplantation: a value proposition

Michael Oellerich
Institute for Clinical Pharmacology, University Medicine Göttingen, Germany

A value proposition for donor-derived cell-free DNA (dd-cfDNA) testing in organ transplantation is outlined. There is a need to improve personalized immunosuppression in organ transplantation to reduce premature graft loss. Biomarkers are needed to better detect rejection, asymptomatic graft injury, and under-immunosuppression. Assessment of minimal necessary exposure to guide tapering and prevent immune activation is also important. There is robust clinical evidence from more than 50 published studies supporting the role of dd-cfDNA for monitoring graft integrity and detection or exclusion of rejection. The value proposition for the patient includes earlier transplant injury intervention, less full blown rejection risk, an alternative to invasive biopsies, personalized immunosuppression with potential for improved long-term outcome. Transplant physicians benefit from better immunosuppressive guidance and having an alternative when biopsies are refused or contraindicated. Further advantages are improved biopsy interpretation, less trial and error changes in immunosuppression, and less time dealing with complications. The laboratory medicine specialist can provide more effective services. Hospital management and insurance companies could benefit from more cost-effective surveillance of transplant recipients. Potential cost savings would be due to fewer biopsies as a result of the high negative predictive value, fewer retransplantations, or less organ failure with return to dialysis. A pathway to implementation and metrics are suggested to measure the effectiveness of dd-cfDNA testing.

11:00 am – 11:30 am

COFFEE BREAK

11:30 am – 01:10 pm

FLASH COMMUNICATIONS SESSION

Chairs: Stavroula Kanoni, London, United Kingdom / Vangelis Manolopoulos, Alexandroupolis, Greece

11:30 am – 11:50 am

How men have stronger bones_ Sry regulation of RANKL expression

Janja Marc, Ljubljana, Slovenia

How men have stronger bones_ Sry regulation of RANKL expression  

Janja Marc
Faculty of Pharmacy, University of Ljubljana, Slovenia

Receptor activator of nuclear factor κB ligand (RANKL) is one of major regulator of osteoclasts activity and bone resorption.  Factors regulating RANKL expression may therefore  indirectly influence bone quality and development of bone diseases. The frequency of osteoporotic bone fracture in men is about half as many fractures as women, at any given age (1). We aimed to find the gender specific regulators of RANKL. The gene tranfection for overexpression of Sry and silencing of Sry by siRNA in human primary osteoblasts followed by luciferase reporter assays and electrophoretic mobility shift assay were employed. 112 human bone samples were examined using immunohistochemical examination and qPCR. We discovered that transcription factor, sex-determining region Y (SRY), regulate RANKL expression and demonstrated that male-specific SRY decreases RANKL expression through direct binding to its 5’-proximal promoter. These results are corroborated by the gene expression in human bone  samples. In osteoporotic men, expression of RANKL is 17-fold higher, which correlates with the  drastically reduced expression (200-fold) of Sry, suggesting that in osteoporotic men, the  upregulation of RANKL is caused by a decrease of Sry. In healthy men, the expression of RANKL is  20% higher than that in healthy women. Our data suggest that gender differences in RANKL  expression and bone quality could be due to the sex-specific transcription factor SRY (2).

  1. Robert A Adler. Osteoporosis in men: a review. Bone Research (2014) 2, 14001; doi:10.1038/boneres.2014.1
  2. Kodric K. et all. Sex-determining region Y (SRY) attributes to gender differences in RANKL expression and incidence of osteoporosis. Experimental & Molecular Medicine (2019) 51:97. https://doi.org/10.1038/s12276-019-0294-3

11:50 am – 12:10 pm

Polycystic ovary syndrome: do phthalates and bisphenol A play role?

Milica Medic-Stojanoska, Nova Sad, Serbia

Polycystic ovary syndrome: do phthalates and bisphenol A play role?

Milica Medić Stojanoska
University of Novi Sad, Faculty of Medicine, Clinical Center of Vojvodina, Clinic for Endocrinology, Diabetes and Metabolic Diseases, Novi Sad, Serbia

Background: The widespread use of plastics made phthalates and bisphenol A (BPA) omnipresent in the environment. The frequent detection of these endocrine disrupting chemicals during biomonitoring studies in the general population are related to greater incidence of obesity, dyslipidemia, insulin resistance and impaired thyroid function which are elements of polycystic ovary syndrome (PCOS).
Objective: The aim of the cross-sectional study was to determine if plastic chemical exposures can contribute to reproductive disorders such as PCOS.
Design: The concentration levels of phthalate metabolites and BPA in morning spot urine of women in reproductive period were determined by gas-chromatography coupled with mass spectrometry.
Results: The half of the examined PCOS women had BPA (48.3%) and phthalate metabolites (51.3%) in their urine. The most detected metabolites were mono‐ethylhexyl phthalate and mono-ethyl phthalate which strongly indicate that women with PCOS are highly exposed to di‐2‐ethylhexyl phthalate and diethyl phthalate. The presence of BPA in urine of PCOS women were associated with insulin serum levels insulin serum levels (p=0.038), elevated HOMA-IR values (p=0.079) and reduced HDL (p=0.061). Also, there was almoust 4 times higher risk for PCOS BPA+ women to have testosterone levels above reference values. Concentration levels of sum of all phthalates metabolites significantly correlated with total cholesterol (p=0.028) and LDL (p=0.07). Only mono-methyl phthalate (MMP) urinary levels were strongly correlated with waist circumference, glucose and insuline serum levels, HOMA-IR and testosterone values.
Conclusions: The obtained results indicate that exposition to BPA and some types of phthalates in PCOS women lead to the increased metabolic risk and consequently may aggravate PCOS clinical complications.
References: Medic Stojanoska M, Milosevic N, Milic N, Abenavoli L. The influence of phthalates and bisphenol A on the obesity development and glucose metabolism disorders. Endocrine. 2017;55(3):666-681.
Acknowledgements:  This work was supported by the Provincial Secretariat for Science and Technological Development, AP Vojvodina, Republic of Serbia (Grant No.  114-451-2394/2011; Grant No. 114-451-2216/2016).
Keywords: plasticizers; endocrine disruptors; fertility

12:10 pm – 12:30 pm

Association between CYP2C19 polymorphisms and clinical outcomes in STEMI patients treated by PPCI

Sanja Stankovic, Belgrade, Serbia

Association between CYP2C19 polymorphisms and clinical outcomes in STEMI patients treated by PPCI

Sanja Stankovic , M. Asanin (2), D. Milasinovic (3), J. Djurovic (4), O. Stojkovic (4), G. Stankovic (2)
(1) Center for Medical Biochemistry, Clinical Center of Serbia, Belgrade, Serbia.
(2) Department of Cardiology, Clinical Center of Serbia, Belgrade, Serbia; Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
(3) Department of Cardiology, Clinical Center of Serbia, Belgrade, Serbia.
(4) Faculty of Medicine, University of Belgrade, Belgrade, Serbia.

Primary percutaneous coronary intervention (PPCI) is nowadays the preferred reperfusion strategy for treating ST-elevation myocardial infarction (STEMI) patients, aiming at restoring epicardial infarct-related artery patency and achieving microvascular reperfusion as early as possible. Clopidogrel is a commonly used antiplatelet drug to reduce the rate of procedure-related thrombosis. The response to clopidogrel varies widely among individuals. Differing responses to clopidogrel may be related to CYP2C19 gene polymorphisms. Although the relationship between CYP2C19*2/CYP2C19*3 alleles and increased incidence of stent thrombosis is well known, CYP2C19*17 impact on clinical outcome is an area that requires more investigation. Our study  was aimed to study the clinical impact of CYP2C19 gene polymorphisms in STEMI patients treated by PPCI. In this prospective single-center study polymorphisms of CYP2C19 and platelet function assessed by Multiple Electrode Aggregometry will be assessed in 140 patients consecutive patients referred to primary PCI for STEMI in a high-volume cath lab. The primary end-points were major adverse cardiovascular/cerebrovascular events (MACE/MACCE) and major bleeding. Our results suggest an increased risk of ischemic events following PPCI in carriers of CYP2C19*17, independent of clopidogrel responsiveness. The data revealed that the combination of CYP2C19 polymorphisms and established clinical risk scores could derive a more accurate prediction for clinical outcomes in STEMI patients. will be also presented.

12:30 pm – 12:50 pm

[MedeA]: Development of a Clinical Support System for PGx clinical Implementation based of e-health

Adrian LLerena, Badajoz, Spain

[MedeA]: Development of a Clinical Support System for PGx clinical Implementation based of e-health

Adrián LLerena MD PhD. Director. Pharmacogenetics and Personalized Medicine Unit, INUBE Extremadura Biosanitary Research Institute, Spain.

The MedeA Initiative is a genuine personalized medicine (PM) clinical implementation programme. It is based on an analysis of each patient’s individual pharmacogenetic biomarkers, drug-drug interactions and clinical data evaluated in an e-health strategy. This information is fed into a software system called Personalized oriented Prescription System (PoPS) integrated within the Electronic Medical Record (EMR) system. It acts as a decision support tool (CDST) suggesting the best drug or drug combination for an individual patient.
The aim is to develop an individualised drug prescription decision supporting tool for regular clinical practice by assessing and analysing pharmacogenetic information and other variables (clinical data and drug prescription) from the EMR with artificial intelligence algorithms. The project is implemented for all patients of the Public Health System in the Spanish region of Extremadura.
This e-health innovation programme involves private companies in its development, by using Innovative Public Procurement to promote R&D&I in companies and within the framework of the Open Innovation Model promoted by the Extremadura Health Care Services and the Spanish Ministry of Science and Innovation (MICINN). This initiative is divided into four Technological Challenges with a total budget of 5.465.747 €:
1) PoPS: Development of a Personalized oriented Prescription System (CDSS Clinical Decision Support System)
2) SiGEN: Development of a set-up for laboratory analysis of pharmacogenetic biomarkers;
3) PePS: Development of a Personalized stratification system for patients and/or healthy volunteers participating in clinical research/trials;
4) SeRAM: Development of tools for clinical evaluation and detection of adverse reactions during daily life based on biosensors (IoT).
This initiative would be applicable to any health care setting developing an automated personalised prescription system promoting drug safety and efficacy. It is conceptualized as a proof of concept for PM implementation and could be taken up by other European health care services, contributing to their sustainability and improving the treatment of patients.

12:50 pm – 01:10 pm

Pharmacogenetics and Personalized Medicine in Anticoagulation: latest developments

Vangelis Manolopoulos, Alexandroupolis, Greece

Pharmacogenomics and Personalized Medicine in Anticoagulation: latest developments

 Vangelis G Manolopoulos, Professor of Pharmacology, Pharmacogenomics, and Precision Medicine
Director, Laboratory of Pharmacology, Medical School, Democritus University of Thrace, & Clinical Pharmacology and Pharmacogenetics Unit, Academic General Hospital of Evros, Alexandroupolis, Greece

In recent years, the therapeutic arsenal for anticoagulation has gradually grown and currently includes, in addition to the older coumarinic anticoagulants (COAs), four novel compounds, the direct thrombin inhibitor dabigatran, and the factor X inhibitors rivaroxaban, apixaban, and edoxaban, collectively referred to as direct oral anticoagulants (DOACs). NOACs have several advantages over COAs, such as fixed-dosing with no need for monitoring, few interactions and a wider therapeutic window, however, disadvantages are not absent, including high cost, limited clinical experience, and lack of standardized test for NOAC monitoring.
Application of COAs PGx is useful both in predicting the optimal doses of COAs and in identifying individuals who are at increased risk of bleeding with COAs and, consequently, would benefit with a DOAC rather than COAs.
Regarding DOAC PGx, so far there have been only sparse data, most notably a GWAS in patients treated with dabigatran, and only a few polymorphic genes have been studied in association with DOAC response. Further developments in anticoagulant PGx are warranted for both COAs and DOACs. In addition, some answers in relation to the heterogeneity in patient responses to both these classes of drugs may be found at the epigenetic level, an emerging area of research in which also our lab is heavily involved wih the oordination of the clinical study “Epigenetic modifications (DNA methylation and miRNAs) as regulators of response to DOACs in atrial fibrillation (The MiR-CRAFT study)”

01:10 pm – 02:30 pm

LUNCH TIME

02:00 pm – 03:00 pm

2nd dedicated poster session

03:00 pm – 04:00 pm

SESSION II

ADVANCES ON CELLULAR AND MULTI-OMIC APPROACHES

Chairs: Behrooz Z. Alizadeh, Groningen, The Netherland / Robert Barouki, Paris, France

03:00 pm – 03:30 pm

Engineering a Rational Approach to Precision Oncology Drugs

Colin Brenan, Boston, Massachusetts, United States

Engineering a Rational Approach to Precision Oncology Drugs

Colin J.H. Brenan1  and O. Jonas1,2
1Kibur Medical Inc., 29 Newbury Street, Room 301, Boston, MA, 02116 USA
2Brigham and Women’s Hospital, Department of Radiology, 75 Francis St. Boston, MA 02115 USA

Clinical trials of new oncology drugs have a staggering 97% failure rate typically due to toxicity or lack of drug efficacy.  One common issue is failure to understand the mechanism of action and misidentification of putative biomarkers indicative of drug response.  To address this issue, we have developed and clinically deployed an innovative implantable microdevice (called the NanonailTM) for functional and simultaneous intra tumor molecular profiling of tumor sensitivity to up to 18 different oncology drugs and/or drug combinations per microdevice at the single cell level and with the tumor in its native microenvironment.  Each unique drug or drug combination is loaded into one of the micromachined depots of the Nanonail for delivery of a controlled dose of drug to the surrounding tumor tissue once inserted into the tumor with a standard fine needle biopsy tool. After 1-3 days the device is recovered with a plug of surrounding tissue and processed according to standard histopathology protocols.  Thin sections of the zone of drug-tumor interaction are individually analyzed to create a detailed, high resolution spatial multi-omic profile of the tumor response to each agent.  An additional benefit, molecular profiling the tumor-drug response along the spatial diffusion profile of drug from each depot provides key information on tumor response to different drug doses. We will provide examples on how application of single cell functional profiling can reveal novel, potent anti-tumor drug combinations and in particular the combination of an immunotherapy with molecularly targeted or cytotoxic agents.

03:30 pm – 04:00 pm

Biomarker discovery in the era of automated machine learning: from targeted to data-driven approaches

Ekaterini Chatzaki, Alexandroupolis, Greece

Biomarker discovery in the era of automated machine learning: from targeted to data-driven approaches

Ekaterini Chatzaki
Alexandroupolis, Greece  

Biomarkers are the cornerstone of precision medicine: identified as a measurable indicator of some biological state or condition, they promise to offer solutions for accurate diagnosis, prognosis and therapeutic monitoring. Among other biological entities, DNA methylation patterns differing dramatically between tissues and changing dynamically over time, are suggested to carry clinically valuable information. We have been studying methylation in liquid biopsy material, ie cell-free DNA liberated in the circulation, in different pathological conditions such as cancer and diabetes. Recently, following the global scientific trend, we move gradually from hypothesis-driven to (big) data-driven approaches, as modern -omics technologies lead the accumulation of large precious multi-parametric biological datasets. We employ ad-hoc auto Machine Learning tools for data extrapolation, delivering low-feature validated models/classifiers. Translational development will lead to emerging cost-effective multiplex bench assays expected to retain high diagnostic performance in a real world setting, readily available for commercialization. Our approach can have unprecedented added value in different medical conditions, such as the Covid-19 pandemic, and/or other biological problems.

04:00 pm – 5:00 pm

SESSION III

APPROACHES FOR THE DISCOVERY OF DRUG TARGETS, RESISTANCE MECHANISMS, AND BIOMARKERS

Chairs: Stavroula Kanoni, London, United Kingdom / Behrooz Z. Alizadeh, Groningen, The Netherland

Sponsored by

04:00 pm – 04:30 pm

Flexible and Scalable Genetic Screens for Discovery and Characterization of Novel Therapeutic Targets

 Paul Diehl, Mountain View, United States

Flexible and Scalable Genetic Screens for Discovery and Characterization of Novel Therapeutic Targets 

Paul Diehl
Cellecta, Inc., Mountain View, California, USA

The measurements of changes in gene activation and expression provide a basis to understand the genetic changes that cause biological responses of interest. Cell-to-cell gene disruption induced by CRISPR and other gene-perturbation technologies help tease out the drivers required for these responses.
We will discuss how adaptations of these two screening approaches can be used to discover the genetic drivers responsible for phenotypic variabilities, such as drug sensitivities, disease variation, and degrees of differentiation within cell populations, across tissue microenvironments, and between single cells.

04:30 pm – 05:00 pm

Immunophenotyping of T Cell Receptor and B Cell Receptor clonotypes

Alex Chenchik, Mountain View, United States

Immunophenotyping of T cell receptor and B cell receptor clonotypes 

Alex Chenchik
Cellecta, Inc., Mountain View, California, USA

T cell receptor (TCR)/B cell receptor (BCR) repertoire profiling holds great potential for understanding disease mechanisms. We introduce a novel technology for profiling of all human TCR and BCR variable regions and phenotypic characterization of immune cells in bulk and at the single-cell level in PBMCs and immune cell fractions. Preliminary data shows that TCR/BCR clonotype analysis combined with targeted expression profiling of immune cells can be applied for large-scale discovery in several immune-responsive model systems.

05:00 pm – 6:00 pm

General Assembly of the Santorini Conferences (SCs) Association

9:00 pm

GALA DINNER at DEMILMAR Beach Restaurant, Perissa

09:30 – 11:00 am

SESSION IV

HEART INFLAMMATION

Chairs: Panagiotis Deloukas, London, United Kingdom / John Lamont, Crumlin, County Antrim, United Kingdom

Sponsored by

09:30 am – 10:00 am

Tracking T cell-mediated autoimmunity in the heart

Federica Marelli-Berg, London, United Kingdom

Tracking T cell-mediated autoimmunity in the heart.

Federica Marelli-Berg
British Heart Foundation Chair of Cardiovascular Immunology, William Harvey Research Institute, London, United Kingdom

Autoimmune cardiac inflammation is becoming recognized as a key contributing factor in heart muscle diseases. Despite advances, the functional features of cardiac immunity in humans remain largely undefined, due to the technical challenges of studying the immune response in-situ. We described a population of cardiotropic T-cells (cT-cells) characterized by the expression of the hepatocyte growth factor receptor cMet and the chemokine receptors CCR4 and CXCR3. Here we show that memory, activated cT-cells significantly increase in the circulation and in the heart of patients with inflammatory cardiomyopathies, but not in acute myocardial infarction or healthy controls. cT-cells divide preferentially in response to the autoantigen cardiac myosin and display similar functional features in acute and chronic cardiac inflammation. In experimental autoimmune myocarditis, which recapitulates the autoimmune phase of human myocarditis, development of cT-cells and disease can be prevented by pharmacological cMet inhibition, suggesting a causative role for this T-cell subset.

10:00 am – 10:30 am

Predictive value of Inflammatory causes of vascular disorders in Personalized medicine

Behrooz Z. Alizadeh, Groningen, The Netherland

Predictive value of Inflammatory causes of vascular disorders in Personalized medicine.

Behrooz Z. Alizadeh, MD, MSc, PhD, VvE
Unit of Personalized Medicine, Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherland.

The pivotal role of inflammation in cardiovascular diseases has been scrutinized for a century. Several inflammatory biomarkers have been associated with the development and/or progression of cardiovascular diseases, or they are used to monitor disease course. Based on these associations, accumulating number of studies suggest the involvement of specific molecular pathways in the disease mechanism, which are represented by inflammatory biomarkers and are claimed potential targets for therapeutics (NFκB, OPN). However, there is little known whether these associations are causal and are dependent on the dominant type of inflammatory cells. And what is the additive value of including inflammatory biomarkers in patient-tailored therapies? I will present the latest results of our studies on the causal association of inflammatory biomarkers with major cardiovascular phenotypes, by using genetic risk scores supplied with experimental studies. Further, I will evaluate the potential application of inflammatory biomarkers in better prediction of disease outcomes. Future investigations should focus on the crosstalk between causal inflammatory biomarkers, the type of inflammatory cell involved, in the pathological contexts of cardiac cells. These studies may eventually lead to specific inflammatory-based therapies for the personalized prevention and treatment of cardiovascular diseases.

10:30 am – 11:00 am

Development of a Type I Diabetes Genetic Risk Array

Helena Murray, Crumlin, County Antrim, United Kingdom

Development of a Type I Diabetes Genetic Risk Array

Yadev R1, Murray HA1, Lamont JV1, Fitzgerald SP1, Oram RA2, Hattersley AT2, Weedon MN2 and Locke JM2
1Randox Laboratories Limited., 55 Diamond Road, Crumlin, Co. Antrim, UK, BT29 4QY
2 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK

Introduction: Differentiating between Type 1 diabetes (T1D) and Type 2 diabetes (T2D) is challenging due to the increasing incidence of childhood obesity blurring the traditional T1D versus T2D timelines. More young people are getting T2D and T1D can occur at any stage in life, but treatment and patient care pathways are very different depending on diabetes type. Besides this, there has been an increasing number of cases of T1D occurring at old age. Currently available diagnostic tests have several limitations in accurately diagnosing diabetes subtypes. Up to 15% of young adults are wrongly classified and treated. The aim of this study was to consider genetic predisposition as an aid to improve diabetes classification.
Genetic predisposition to diabetes is largely determined by the presence of human leukocyte antigen (HLA) genes. A number of Single Nucleotide Polymorphisms (SNPs) that tag these genes have been shown to identify increased risk. Genome-wide association studies have identified additional non-HLA SNPs, robustly linked with T1D. Combining these, a 10 SNP genetic risk score (GRS) was developed which can aid discrimination between T1D and T2D, particularly when used in conjunction with clinical features and autoimmune markers.
Materials and Methods: The assay employs multiplex Polymerase Chain Reaction (PCR) coupled to Biochip Array Technology (BAT, Randox Laboratories Ltd, Crumlin, UK) to genotype 10 SNPs associated with T1D (Oram et al.,2016). Multiplex SNP-specific PCR amplicons are hybridised and spatially separated onto a grid of discrete test regions on a biochip, followed by chemiluminescent detection on the Evidence Investigator analyser. Assay run time is <3 hours from DNA template to generation of SNP genotypes. Assay optimisation and specificity was realised using pre-characterised DNA samples and initially validated by testing DNA samples (n=259) provided by University of Exeter, with results compared against genotypes using an alternative method.
Results: The Type 1 Diabetes GRS array is capable of rapidly detecting all 10 SNPs associated with T1D. Using the biochip array, all 259 samples (2590 genotypes) were in agreement (99.9%) with genotypes predicted by University of Exeter. Samples tested covered all the genotypes linked to 10 SNPs.
Conclusion: The Type 1 Diabetes GRS array provides a rapid and reliable genotyping test for detecting 10 SNPs associated with T1D. Through an associated algorithm, the array can generate a T1D Genetic Risk Score, which in conjunction with conventional methods, can distinguish T1D from other subtypes. This assay has potential to prevent misdiagnosis of diabetes and facilitate improved patient management.

11:00 am – 11:30 am

COFFEE BREAK

11:30 am – 12:30 pm

SESSION V

ECON-OMICS: BETTER CARE FOR BETTER COST

Chairs: Georges Dagher, Paris, France / Robin Everts, San Diego, United States

11:30 am – 12:00 pm

Big data, Artificial Intelligence and ethics

Georges Dagher, Paris, France

Big data, Artificial Intelligence and ethics

Georges Dagher
Inserm, France
Graz Medical University
Milano-Bicocca University
Beijing Academy of Sciences

Big data are certainly an essential component of digital science and technology and also of machine learning, robotics, and new means of communication. They are also part of the digital revolution that is shaking our society to its very roots. The information that the data initially contain, is considerably enriched by cross-referencing data. Highly diverse, these data can be related to health or well-being.
One of the characteristics of big data in health is the blurring of the distinctions underpinning implementation of the ethical principles that promote the protection of individual rights in health. Precise knowledge of individuals and of their state of health creates a risk of profiling, which threatens the protection of private life and may lead to stigmatization of people or groups. Such stigmatization threatens private life, but also the principles of solidarity and equity which are the basis of our health system. Care and business are becoming increasingly hard to distinguish, as a result of the transformation of care and of the healthcare market.
In addition, ethical principles can be weakened by the exploitation of big data: medical confidentiality, the responsibility of the medical decision and the personal relationship between the doctor and patient.
The need for protection of the individual must be reaffirmed and its modalities redefined, to dispel the threat of a society under the surveillance and control of multiple providers acting for various purposes.

12:00 pm – 12:30 pm

Standardized Preanalytics: The Key for Reliable Diagnostics, Research and Biobanking

Uwe Oelmueller, Hilden, Germany

Standardized Preanalytics: The Key for Reliable Diagnostics, Research and Biobanking

Uwe Oelmueller
QIAGEN GmbH, MDx Sample Technologies, 40724 Hilden, Germany

Molecular in vitro diagnostics and research have allowed great progress in medicine including diagnostics. Further progress is increasingly established by new biomarker tests analyzing specimens’ biomolecule profiles such as nucleic acids, proteins, and metabolites. However, profiles of these molecules can change significantly during specimen collection, transport, storage, and processing, caused by post collection cellular changes such as gene inductions, gene down regulations, biomolecules modifications or degradation. This can make the outcome from diagnostics or research unreliable or even impossible because the analytical test will not determine the situation in the patient body but an artificial specimen analyte profile generated during the pre-analytical workflow. Preanalytical variables are a major error source for wrong diagnostic test results. High quality specimens with preserved analyte profiles are therefore crucial for reliable diagnostics, biomedical research and biobanking. Specifying, developing and verifying pre-analytical workflow parameters for diagnostics tests has consequently become a requirement by new European legislation.
The EU SPIDIA Consortium (2008-2013) developed new pre-analytical technologies for preserving molecular profiles in human specimen and generated broad evidence that guidance to laboratories on pre-analytical workflows improves analytical test results. Based on these results, the CEN/TC 140 for “in-vitro diagnostic medical devices” had released first 9 European Technical Specifications for pre-analytical workflows addressing different blood, other body fluids and tissue based molecular applications. In 2018 and 2019 they progressed to International Standards at the ISO/TC 212 for “clinical laboratory testing and in vitro diagnostic test systems”. The successor EU SPIDIA4P consortium project (2017-2021), supported by a large international network, has broadened to a final portfolio of 22 pre-analytical CEN and ISO Standards intending to improve in vitro diagnostics and biomedical research, has developed corresponding External Quality Assurance (EQA) and is driving international implementation. The new standards can serve to fulfill requirements in the new EU In Vitro Diagnostic Regulation 2017/746 (IVDR). The SPIDIA4P project has received several awards including the “CEN-CENELEC Standards+Innovation Project Award 2021” for its important contribution of research and innovation to standardization.
The SPIDIA project received funding from the EU’s FP7 under grant agreement no. 222916. The SPIDIA4P project received funding from the EU’s Horizon 2020 research and innovation program under grant agreement no. 733112.

 

12:30 pm – 01:30 pm

SESSION VI – 1st part

GENETIC SCREENING & CLINICAL APPLICATIONS

Chairs: Guillaume Paré, Hamilton, Canada / Georges Dedoussis, Athens, Greece

12:30 pm – 01:00 pm

Digging deep for translational gold: Multi-omics approach to cardio-metabolic traits

Guillaume Paré, Hamilton, Canada

Digging deep for translational gold: Multi-omics approach to cardio-metabolic traits

Guillaume Paré
Canada Research Chair in Genetic and Molecular Epidemiology, Cisco Professorship in Integrated Health Biosystems, Senior Scientist, Population Health Research Institute , Genetic and Molecular Epidemiology Laboratory, McMaster University, Hamilton, Ontario, Canada

Despite recent advances in acute diagnosis and treatment of cardio-metabolic diseases (CMD), the development of new blood biomarkers for risk stratification has been slow. The majority of reported biomarker-disease associations fail to enter clinical practice due to their inabilities to discriminate risk, or more importantly, due to a lack of evidence that they represent causal associations with risk of disease. This latter pitfall is particularly damning as the lack of causality prevents conclusions about the benefit of interventions to decrease putative risk factors, and also make the disease association itself vulnerable to known or unknown confounders. Distinguishing modifiable, causal mediators from the many biomarkers that are statistically linked to CMDs is a primary challenge in molecular epidemiology. Even the strongest epidemiological associations do not imply causation, making the discovery of modifiable risk factors difficult. However, truly causal biomarkers such as LDL cholesterol have been invaluable in the prevention, treatment and identification of at-risk individuals. We propose an integrated genomic-proteomic (biomarker) approach to identify novel causal mediators of CMDs, and illustrate with examples from coronary artery disease, stroke, diabetes, chronic kidney disease and obesity. Our approach is based on Mendelian Randomization (MR), a statistical genetics method that uses genetic associations with both the putative causal factor (i.e. exposure) and the cardiovascular outcome to infer causality. MR protects against confounding and reverse causation. Integrating genetics and high-throughput proteomics holds the promise of better risk stratification, identification of new disease pathways, and paves the way for novel therapeutic interventions.

01:00 pm – 01:30 pm

Omics and Mastiha treatment in NAFLD – The EU Mast4Health program

Georges Dedoussis, Athens, Greece

Omics and Mastiha treatment in NAFLD – The EU Mast4Health program

C Amerikanou1, S Kanoni2, AC Kaliora1, A Barone3, M Bjelan4, G D’Auria5,6, A Gioxari1, MJ Gosalbes6,7, S Mouchti3, MG Stathopoulou8, B Soriano9, S Stojanoski4,10, R Banerjee3, M Halabalaki11, EV Mikropoulou11, A Kannt12-14, J Lamont15, C Llorens9, F Marascio16, M Marascio, FJ Roig9,17, I Smyrnioudis18, I Varlamis19, M Vukic20, N Milic4, M Medic-Stojanoska4,21, L Cesarini22, J Campolo23, A Gastaldelli24, P Deloukas2,25, MG Trivella23,24, MP Francino6,7, S Visvikis-Siest8 MAST4HEALTH consortium, George V Dedoussis1.

1Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, Athens, Greece, 2William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, EC1M 6BQ, UK, 3Perspectum Ltd, Oxford, UK, 4Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia, 5Sequencing and Bioinformatics Service, Fundació per al Foment de la Investigació Sanitària i Biomèdica de la Comunitat Valenciana (FISABIO- Salut Pública), Avda. Catalunya 21, València, 46020, Spain, 6CIBER en Epidemiología y Salud Pública, Av. Monforte de Lemos 3-5, Madrid, 28029, Spain, 7Joint Research Unit in Genomics and Health, Fundació per al Foment de la Investigació Sanitària i Biomèdica de la Comunitat Valenciana (FISABIO) and Institut de Biologia Integrativa de Sistemes (Universitat de València / Consejo Superior de Investigaciones Científicas), Avda. Catalunya 21, València, 46020, Spain, 8UMR INSERM U1122; IGE-PCV, University of Loraine, Nancy, France, 9Biotechvana, Parc Científic, Universitat de València, Paterna, Valencia, Spain, 10Centre for Imaging Diagnostics, Oncology Insitute of Vojvodina, Sremska Kamenica, Serbia, 11Division of Pharmacognosy and Natural Products Chemistry, Department of Pharmacy, National and Kapodistrian University of Athens, Athens, Greece, 12Sanofi Research and Development, Industriepark Hoechst, Frankfurt, 65926, Germany, 13Institute of Clinical Pharmacology, Goethe University Frankfurt, Frankfurt, 60590, Germany, 14Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt, 60596, Germany, 15Randox Laboratories Limited, Crumlin, Co. Antrim, Northern Ireland, UK, 16Marascio Fernando, Intervideo, Catanzaro, CZ, 88100, Italy, 17Facultad de Ciencias de la Salud, Universidad San Jorge, Zaragoza, 50830, Spain, 18Chios Mastic Gum Growers Association, Chios, Greece, 19Department of Informatics and Telematics, Harokopio University, Athens, Greece, 20Department of Food Technology, Faculty of Technology Zvornik, University of East Sarajevo, Zvornik, 75400, Bosnia and Herzegovina, 21Clinic for Endocrinology, Diabetes and Metabolic Diseases, Clinical Centre of Vojvodina, Novi Sad, Serbia, 22Division of Hepatology and Gastroenterology, Niguarda Ca’ Grande Hospital Milan, Italy, 23Institute of Clinical Physiology, CNR, Milan, Italy, Cardiometabolic Risk Unit, Institute of Clinical Physiology, CNR, Pisa, Italy 25Centre for Genomic Health, Life Sciences, Queen Mary University of London, London, UK. 

Background: Nonalcoholic fatty liver disease (NAFLD) is a major public health concern in both industrialized and developing nations, with an estimated global incidence of 25% in the general population and with limited treatment approaches.
Objective: We investigated the effect of the nutraceutical Mastiha supplement (2.1 g/day for a total of 6-months) in the omics profile of patients with NAFLD.
Design: MAST4HEALTH was set on the concept of a multidisciplinary approach to assess a non-pharmacological nutraceutical intervention for managing NAFLD/NASH. Within a multicenter, randomized, double-blinded, and placebo-controlled clinical trial design MRI disease parameters, biochemical, and multi-omic analyses were performed.
Results: Improvement in liver inflammation and fibrosis was reported byMRI scanning and the use of the sensitive LiverMultiScan software. Post-treatment levels of both Liver Inflammation Fibrosis score (LIF) and iron-corrected T1 (cT1) were lower in Mastiha compared to the Placebo in BMI>35 kgm-2. The Bray-Curtis dissimilarity index between baseline and post-treatment bacterial communities was larger in Mastiha versus Placebo. Mastiha improved microbiota dysbiosis mainly through decreasing the abundance of inflammatory taxa. As intestinal microbiota dysbiosis is well-established in NAFLD pathogenesis, modification in microbiota composition is important in the resolution of the disease. The metabolomic analysis showed a significant reduction of Lysophosphatidylcholines and Lysophosphatidylethanolamines in the Mastiha group suggesting that Mastiha exhibits a beneficial effect in phospholipid homeostasis. A very significant post treatment increase in a Mastiha derived metabolite (sulpho-conjugated) within the Mastiha group compared to the Placebo has been detected and remained robust across the sensitivity analysis. Mastiha supplementation improved the TAS levels among NAFLD patients with severe obesity.
Conclusions: In conclusion, after six months of Mastiha supplementation, we observed a significant improvement on microbiota dysbiosis and lipid metabolite levels in patients with NAFLD. The beneficial effect on the microbiota parallel with a decrease in plasma cholic acid and phospholipids, may be attributed to the bioavailable triterpenic acids of Mastiha.
(NCT03135873, www.clinicaltrials.gov)
Acknowledgements: This project received funding from the European Union’s Horizon 2020 research and innovation program MAST4HEALTH under the Marie Skłodowska-Curie grant agreement no 691042.

01:30 pm – 02:30 pm

LUNCH TIME

02:30 pm – 04:00 pm

SESSION VI – 2nd part

GENETIC SCREENING & CLINICAL APPLICATIONS

Chairs: Guillaume Paré, Hamilton Canada / Csilla Sipeky, Brussels, Belgium

02:30 pm – 03:00 pm

Polygenic Risk Scores, application and challenges in cardiovascular disease prediction

Panagiotis Deloukas, London, United Kingdom

Polygenic Risk Scores, application and challenges in cardiovascular disease prediction

Panagiotis Deloukas
William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse square, EC1M 6BQ, UK

14% of adults above the age of 16 have doctor-diagnosed cardiovascular disease (CVD) which is a leading cause of death (~25% of all deaths) and disability in the UK. Coronary Heart Disease (CHD) is the leading cause of CVD death in both sexes (14% men, 8% women). South-Asians have a 2-fold higher risk for CHD compared to European-descent individuals and an earlier onset of disease.
A polygenic risk score (PRS) aggregates all known changes associated to the disease as a tool for people to learn about their risk of e.g. developing CHD. We developed a European CHD-PRS using the data from the latest CARDIoGRAMplusC4D meta-analysis in 1,165,690 participants including 181,522 cases (2.3m markers). Evaluation of this new CHD-PRS in the Malmo Diet and Cancer study (n=22,872; CHD_cases=3,307) confirmed its predictive value based on established measures (area-under-the curve of 0.74; age- and sex-adjusted mean hazard ratio of 1.56) and demonstrated its ability to predict secondary cardiovascular events. LDL-cholesterol is a major CHD risk factor. In a parallel study of LDL-cholesterol in 1.65m individuals, we showed that the trans-ethnic PRS had the best or near-best performance in each ethnic group tested, with improved or equivalent prediction relative to ancestry-matched scores. We validated this in 25,000 British South Asians using our Genes & Health cohort (Nature, 2021).
We are further developing trans-ethnic CHD PRS and aim to validate its performance in 49,000 British South Asians. Whilst pursuing investigation of disease prevention in the British population, we are assessing the cost-effectiveness and clinical value of the CHD-PRS in improving management of those with established disease. As part of a national UK effort (Our Future Health programme) we will look at disease severity and onset (e.g. premature CHD) in patients with higher PRS (+/- risk factors) including rare CV diseases.

03:00 pm – 03:30 pm

The relevance of non-genomic stressors: deciphering environmental factors for the next decade

Robert Barouki, Paris, France

The relevance of non-genomic stressors: deciphering environmental factors for the next decade

Robert Barouki
Université de Paris, Inserm unit 1124 (T3S), Paris, FRANCE

Climate change, urbanisation, chemical pollution and disruption of ecosystems, including biodiversity loss, affect our health and wellbeing. HERA is an EC-funded H2020 CSA project aiming at providing a research agenda for the next ten years in the field of environment climate and health (https://www.heraresearcheu.eu/). The agenda identifies six major research goals in these fields. These include research to 1) reduce the effects of climate change and biodiversity loss on health and environment, 2) promote healthy lives in cities and communities, 3) eliminate harmful chemical and physical exposures, 4) improve health impact assessment and implementation research, 5) develop infrastructures, technologies and human resources and 6) promote research on transformational change towards sustainability. Numerous specific recommendations for research topics are presented under each research goal. The results call for an unprecedented effort to support a better understanding of the causes, interlinkages and impacts of environmental stressors on health and the environment. This will require breakdown of silos within policies, research, actors as well as in our institutional arrangements in order to enable more holistic approaches and solutions to emerge.

03:30 pm – 04:00 pm

Genetic susceptibility for COVID-19 infection and severity

Stavroula Kanoni, London, United Kingdom

Genetic susceptibility for COVID-19 infection and severity

Stavroula Kanoni1
1William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse square, EC1M 6BQ, UK

The COVID-19 pandemic, caused by infection with SARS-CoV-2, has led to a total of 373 million cases worldwide and 5.5 million deaths. The pandemic resulted to an unprecedented global health crisis. Scientists joined forces for the most comprehensive investigation of this virus. The SARS-CoV-2 infection has varied consequences, ranging from asymptomatic, to mild flu-like symptoms, to life-threating consequences like viral pneumonia and acute respiratory distress syndromes.

Risk factors associated with the disease severity include increasing age, being a man, other comorbidities (cardiovascular disease, diabetes, obesity, cancer, chronic lung disease) and ethnicity. Furthermore, host genetic factors have also been identified as risk factors of SARS-CoV-2 infection or severe consequences of COVID-19, through genome-wide association studies (GWAS), whole-genome sequencing (WES) and candidate gene studies. Genetic investigations from large collaborative consortia, like the COVID-19 Host Genetics Initiative (HGI), the Genetics Of Mortality In Critical Care (GenOMICC), and the COVID human genetic effort among others, have implicated several genes with infection susceptibility or disease severity. These genes are involved in key pathophysiological processes, including viral entry into cells, immunity, and inflammatory responses. The most putative causal COVID-19 genes include SLC6A20, ABO, CXCR6, INFAR2, OAS (1,2,3), DPP9, TYK2, ACE, MUC5B and FOXP4 and are linked to increased susceptibility and/or severity.

Genetic studies have also investigated the shared genetic architecture between COVID-19 and other health conditions through electronic health record data. Genetic predisposition to severe COVID-19 was associated with deep venous thrombosis, morbid obesity, renal failure, pulmonary heart disease and respiratory failure. Large scale observational and Mendelian randomization studies have identified smoking as a risk factor for infection and severity, while there is no protective effect of vitamin D on COVID-19 susceptibility, severity, or hospitalization.

The development of vaccines against SARS-CoV-2 have proven very efficient at halting the spread with almost 10 billion doses administered worldwide so far. The emergence of mutated variants of the virus are causing concern but vaccine engineering could be implemented to match the need of a response to the new variants. It is very crucial to increase the genomic surveillance around the world and at the same time increase the vaccine uptake. Furthermore, precision medicine has the potential of improved COVID-19 prognosis through monoclonal antibodies treatments.

04:00 pm – 05:45 pm

SELECTED ABSTRACTS – ORAL COMMUNICATIONS SESSION

Chairs: Stavroula Kanoni, London, United Kingdom / Belgin Süsleyici, Istanbul, Turkey

04:00 pm – 04:15 pm

A Prospective Multicenter French Study of the 21-Gene Assays: Impact on Treatment Selection in Patients with High-Risk Breast Cancer

Didier Bourgeois, Neuilly-Sur-Seine, France

A Prospective Multicenter French Study of the 21-Gene Assays: Impact on Treatment Selection in Patients with High-Risk Breast Cancer

Didier Bourgeois
Surgical Dpt, Henri Hartmann Breast Institute, Neuilly-Sur-Seine, FRANCE

Objective: The 21-gene Oncotype DX Recurrence Score has been extensively validated to predict the risk of distant recurrence and the magnitude of response to hormone and chemotherapy in patients with ER+ N0 and N1-3+ HER2- early stage breast cancer. Outcomes data from multiple large studies further confirm the assays clinical validity and utility. The test is available in France via the French public funds program (RiHN) and a market access program is in place that collects data countrywide regarding test utilization in clinical practice. This analysis is focused upon clinically high-risk patients according to traditional pathologic criteria.
Method: The online market access database program prospectively collects patient information including traditional clinical and pathological features (histology, tumor grade, size, ER, PR, HER2 status and % of Ki67), patient age as well as the 21-gene Recurrence Score Result and treatment recommendations before testing and final therapy prescribed after Recurrence Score results are known.
Results: Data are available in 786 patients of which 148 had high-grade (G3) tumors and 249 patients had a high KI67 (>20%). In this cohort 122 (87%) and 159 (75%) of patients with G3 and high KI67 features respectively, had pre-ODX treatment recommendations for chemo-hormonotherapy (CT-HT). Post-ODX testing recommendations for CT-HT decreased to 82 (58%) and 95 (45%) for patients with G3 and high KI67 respectively. This finding highlights that testing results in sparing a significant number of patients unnecessary CT. Indeed, post-testing physicians changed treatment decision in 35% and 40% of patients with G3 and high KI67 disease leading to a 28% and 30% net reduction in CT respectively. This provides physicians with confidence in making important treatment decisions, with 83% and 82% HT alone among RS<18, 93% and 98% CT-HT among RS>30 and 37% and 45% HT alone among RS18-30 for G3 and KI67>20% respectively.
Conclusions: The 21-gene test provides critical information that changes and supports final treatment decisions in breast cancer patients identified as high-risk according to traditional tumor grade and high Ki67 levels.

04:15 pm – 04:30 pm

Molecular mechanisms underlying dyslipidemias as risk factors for Alzheimer’s disease

Frances T. Yen, Vandoeuvre-lès-Nancy, France

Molecular mechanisms underlying dyslipidemias as risk factors for Alzheimer’s disease

Frances T Yen1, Ameziane Herzine1, Héla Safi2, Catherine Corbier1, Sandrine Boschi2, Hortense Mazon2, Sophie Visvikis-Siest3
1EA3998 USC INRAE 0340 URAFPA, Université de Lorraine, Vandoeuvre-lès-Nancy, FRANCE
2UMR 7365 CNRS IMoPA, Université de Lorraine, Vandoeuvre-lès-Nancy, FRANCE
3 EA_1122; IGE-PCV, Université de Lorraine, Nancy, FRANCE

Lipid homeostasis is important in health and disease. When dysregulated, this can lead to dyslipidemias, including hypercholesterolemia, hypertriglyceridemia or both (mixed hyperlipidemia). Dyslipidemias are established risk factors for cardiovascular disease, and recent evidence reveal an important impact of age-related cognitive decline and Alzheimer’s disease (AD). However, underlying molecular mechanisms remain unclear – how can changes in peripheral lipid status lead to age-related neurodegenerative processes? A significant clue is provided by apolipoprotein (apo)E, a key protein involved in lipoprotein transport both in peripheral tissues and the brain, serving as ligand for lipoprotein receptors to ensure delivery of lipids to the different tissues. Indeed, the three allelic variants of APOE have been linked to type III hyperlipidemia (e2), high plasma cholesterol levels and AD risk (e4). Lipoprotein receptors involved in regulating apoE-lipoprotein trafficking could therefore represent interesting therapeutic targets for treatment of dyslipidemias and AD.
The human LSR gene is located upstream of the APOE gene, and results reveal epistatic interactions between LSR and APOE that can influence blood lipid levels and AD risk in human subjects (1). This gene codes for the lipolysis stimulated lipoprotein receptor (LSR), a multimeric complex that binds ApoB or ApoE-containing lipoproteins for endocytic processing. Heterozygote lsr+/- mice demonstrate moderate hypercholesterolemia and hypertriglyceridemia, due to a decrease in hepatic removal of lipoproteins and increased body fat mass (2). Furthemore, transcriptomic analysis reveals that these animals have a predisposition to obesity (3). lsr+/- mice reveal age-related changes in brain cholesterol distribution, and increased memory deficits following amyloid stress correlated with cortical cholesterol levels (4). Recent results show a role of LSR in glia/neuron communication through regulation of cholesterol trafficking.
Taken together, these results suggest that the LSR pathway may represent an important molecular link between dyslipidemias, age-related cognitive decline and AD. In addition, the genetic link between APOE and LSR points towards a potential biological and functional relationship between the two gene products that could directly affect not only peripheral lipid homeostasis, but also risk for AD. Further investigation may reveal reliable lipid biomarkers with predictive values for AD allowing timely intervention for reducing AD risk.

Keywords : lipid homeostasis, lipoprotein receptors, cholesterol, apoE, brain aging

References : 1. Xie T, et al. Epistatic interaction of apolipoprotein E and lipolysis-stimulated lipoprotein receptor genetic variants is associated with Alzheimer’s disease. Neurobiol Aging. 69:292.e1-292.e5, 2018., 2. Yen FT, et al. Lipolysis stimulated lipoprotein receptor: a novel molecular link between hyperlipidemia, weight gain, and atherosclerosis in mice. J Biol Chem. 283:25650-25659, 2008., 3. Akbar S, et al. Expression profile of hepatic genes related to lipid homeostasis in LSR heterozygous mice contributes to their increased response to high-fat diet. Physiol Genomics. 48:928-935, 2016., 4. Pinçon A, et al. Increased susceptibility of dyslipidemic LSR+/- mice to amyloid stress is associated with changes in cortical cholesterol levels. J Alzheimers Dis. 45:195-204, 2015.

04:30 pm – 04:45 pm

Perfusable 3D-bioprinted glioblastoma model for in-vivo mimicry of tumor microenvironment and personalized medicine

Lena Neufeld, Tel Aviv, Israel

Perfusable 3D-bioprinted glioblastoma model for in-vivo mimicry of tumor microenvironment and personalized medicine

Lena Neufeld1, E Yeini, N Reisman1, Y Shtilerman1, D Ben-Shushan1, S Pozzi1, A Madi2, R Grossman3, Z Ram3, R Satchi-Fainaro1,4*
1 Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel   Aviv, Israel.
2 Department of Pathology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
3 Department of Neurosurgery, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
4 Sagol School of Neurosciences, Tel Aviv University, Tel Aviv, Israel. 

Background: Many drugs and chemical compounds show promising results in laboratory research, but eventually fail clinical trials. We hypothesize that one main reason for this translational gap is that current cancer models are inadequate. Most models lack the tumor-matrix interactions, which are essential for proper representation of cancer complexity.
Objective: We recapitulated the tumor heterogenic microenvironment by creating a 3D-bioprinted glioblastoma (GB) model. We created a library of synthetic, natural and chemically modified polymers which were used as bioinks.
Design: Fibrin bioink consisting of patient-derived GB cells, astrocytes and microglia. Additionally, perfusable blood vessels were created using a Pluronic F127 polymer coated with pericytes and endothelial cells.
Results: We studied the interactions between each chemical component on the crosslinking kinetics, the mechanical strength of the printed structure and many other properties to match the brain tissue characteristics. Moreover, we observed similar growth curves, drug response and genetic signature of GB cells grown in our 3D-bioink platform and in orthotopic mouse models of cancer as opposed to 2D culture on rigid plastic plates.
Conclusions: Our 3D-bioprinted model could be the basis for potentially replacing cell cultures and animal models as a powerful platform for rapid, reproducible and robust target discovery tool, personalized therapy screening and drug development.
Acknowledgements: The Satchi-Fainaro laboratory’s research leading to these results has received funding from Morris Kahn Foundation.
References: Neufeld L. et.al. “Microengineered Per-fusable 3D-Bioprinted Glioblastoma Model for in vivo Mimicry of Tumor Microenvironment”. Science Advances, 2021.

04:45 pm – 05:00 pm

New ways of implementing PGx to clinical practice with an interactive web application

Wolfgang Schnitzel, Niederalm, Austria

New ways of implementing PGx to clinical practice with an interactive web application

Wolfgang Schnitzel
PharmGenetix GmbH, Niederalm, Austria

Background: The effects and tolerability of medications and their active ingredients can vary greatly from person to person. The reason for this lies in the individual genes of each person. A pharmacogenetic analysis provides important information about the personalized use of medications. Treatments can be optimally adapted, making them safer and more effective. However, physicians are usually not trained in pharmacogenetics and therefore it’s challenging to translate PGx data into tailored dose adaptions in the medical practice. Furthermore, PGx-based drug-drug interactions play a key role in drug metabolism and should therefore also be considered for a solid personalized drug prescription. The lack of PGx knowledge in the medical society and the complexity of PGx reports are significant hurdles to broadly implement PGx into the medical routine. We report from clinical experiences of an in-house developed web application which illustrates the results of a PGx analysis in an easy and actionable way. This web application (PGx-Optimizer) offers information on recommended drug dosages, as well as possible drug-drug interactions.
Objective: Evaluate the clinical usability of an interactive web application which provides physicians with clear and actionable information. It displays which drugs are suitable for the individual patient and whether dose adjustments are necessary based on the patient’s PGx profile. The web  application also takes drug-drug interactions into account.
The objective is to prove that a digital tool like the PGx-Optimizer can allow physicians to understand the consequences of a PGx report, reduces the physician’s spent time on the report’s interpretation and finally facilitate the implementation of PGx into daily routine.
Design: The results of PGx analyses were provided to hospital-based and office-based physicians via the PGx Optimizer. The physicians were given a crash course on PGx and on the functionality of the PGx-Optimizer. They also received support for the interpretation of the original PGx report. A questionnaire was designed in order to collect standardized feedback on the physician’s experience and evaluate the usability of the web application. In addition, clinical effects based on PGx-Optimizer guided adjustments were reviewed in specific patient study cases.
Results: Most of the users rated the PGx-Optimizer as an excellent tool to implement pharmacogenetics. Many physicians reported a noticeable clinical impact for specific patient cases in the context of reduced drug side effects after PGx-guided dose adjustments.
Conclusions: For a broader acceptance and usage of pharmacogenetics in daily medical routine, a digital tool providing clear and actionable recommendations is key. The PGx-Optimizer proved its clinical usability and could therefore serve as a door opener for broader PGx implementation.

 

Reference: www.pharmgenetix.com  

05:00 pm – 05:15 pm

Evaluation of Carboxylesterase-1 and Latrophilin-3 Gene Polymorphisms for Methylphenidate Treatment Prediction in Childhood Attention Deficit Hyperactivity Disorder in Turkish Population

Demet Akin, Istanbul, Turkey

Evaluation of Carboxylesterase-1 and Latrophilin-3 Gene Polymorphisms for Methylphenidate Treatment Prediction in Childhood Attention Deficit Hyperactivity Disorder in Turkish Population

Demet Akin 1, I Suzer2, G Bulut3, A Hodzic1, C Hizel4,5
1. Bahçeşehir Üniversitesi (BAU) Medical School, Istanbul, Turkey 2. Erenköy Mental and Neurological Diseases Hospital, Istanbul, Turkey 3. Karabuk Universitesi, Faculty of Health Science, Karabuk, Turkey 4. OPTITHERA, Inc, Montreal, QC, Canada

Attention deficit/hyperactivity disorder (ADHD) is a childhood-onset behavioral and neurodevelopmental disorder (NDD). Worldwide, ADHD affects approximately 5 % of children that is characterized by inattention, hyperactivity, and impulsivity. The precise cause or causes are unknown in most cases; however, genetic factors are estimated to make up about 75% of the etiology of ADHD that is explained by single nucleotide polymorphisms (SNPs) in regulatory regions rather than coding regions. Besides genetic factors it is anticipated that environmental risk factors likely work through epigenetic mechanisms. Psychostimulants are the first-line pharmacotherapy for ADHD.  Methylphenidate (MPH) accounts for approximately 50% of all stimulant usage worldwide in childhood ADHD that exerts its therapeutic effect by blocking dopamine transporters (DAT) and norepinephrine transporters (NET). However, there is a considerable interindividual variability exists in MPH treatment. Up to 35% of ADHD patients do not respond satisfactorily to MPH therapy, and a significant number of patients suffer from different adverse effects such as, decreased appetite, nausea, headache, insomnia causing to treatment discontinuous. It is reported that polymorphisms in carboxylesterase 1 (CES1) gene and in latrophilin 3 (LPHN3) are associated with response to MPH. In this study, we aimed to is to evaluate the association between MPH therapeutic outcomes in childhood ADHD response and genetic variants of CES1 and LPHN3 in Turkish population by revealing key associations between CES1 and LPHN3 genotypes and PK and PD of MPH, respectively. This study includes 200 patients (70% boys), aged 6 to 17 years, newly diagnosed (medication-naïve) with ADHD according to the DSM-5. After obtaining written consent from parents, saliva sample is collected through buccal swabs for genomic DNA preparation and for genotyping to detect SNPs rs71647871; rs3815583; rs2307227 for CES1 and SNPs rs6551665, rs1947274, rs6858066, rs2345039 for LPHN3. To the best of our knowledge, there are no studies in this kind in Turkish population, so we believe that our study will fill in an important gap in ADH PGx research and will provide the psychiatrists with genotype information to determine suitable dose adjustment for more personalized MPH therapy.

References: Elsayed NA, Yamamoto KM, Froehlich, TE Genetic Influence on Efficacy of Pharmacotherapy for Pediatric Attention-Deficit/Hyperactivity Disorder: Overview and Current Status of Research. CNS Drugs 2020; 34: 389–414.

 

 

05:15 pm – 05:30 pm

Clinical exome sequencing in the African setting: challenges and opportunities

Reem Hamad, Khartoum, Sudan

Clinical exome sequencing in the African setting: challenges and opportunities

Reem Hamad, M Ibrahim and A Hussein
Department of Molecular biology, Institute of Endemic Diseases, University of Khartoum, Khartoum, Sudan.

Introduction and objectives: Africa’s socio- economic conditions, meager health resources and inefficient health system is perhaps not the ideal situation to foster adoption of new genomic technologies, molecular diagnostics and genetic clinics. However, its spectacular genetic variation might render it imperative to implement such approaches if we are to reach accurate diagnosis and satisfactory clinical outcomes.
Methods: Exome and whole genome sequencing were adopted both in research and in clinical diagnostic settings to investigate various familial conditions and genetic abnormalities.
Results and Discussion: Exome and Whole genome analysis revealed disparate and complex etiologies some of unusual genotype phenotype relationships. This relationship reflects the continent legacy of genetic and epigenetic heterogeneity and complexity bearing in mind Africa large effective size and excess of minor reference allele.
Conclusion: There must be a change in our perspective on diagnosing diseases and genetic disorders in Africa building on its population genetic heterogeneity and embarking on serious investments in public health genomics.
Bibliographic references: Koko M, Abdallah MOE, Amin M, Ibrahim M. Challenges imposed by minor reference alleles on the identification and reporting of clinical variants from exome data. BMC Genomics. 2018;19(1):46. Published 2018 Jan 15. doi:10.1186/s12864-018-4433-3
Keywords: Exome sequencing, Public Health Genomics Africa

05:30 pm – 05:45 pm

A machine learning method estimating the benefit of adjuvant therapy in breast cancer

Balazs Gyorffy, Budapest, Hungary

A machine learning method estimating the benefit of adjuvant therapy in breast cancer

Balazs Gyorffy
Rcns, Institut of enzymology, Budapest, Hungary

Background. Different treatment regimens can improve outcome in breast cancer. However, in multiple instances there is no established protocol for the selection of the most suitable treatment for an individual patient. Here, we created a model that provides personalized survival and treatment response estimation based on available clinical and pathological parameters for a breast cancer patient.
Methods. Data was integrated from multiple repositories and databases (TCGA-CDR, SEER, METABRIC, IMPACT, GSE96058). K-means clustering analysis was employed to identify clinically relevant clusters. Multi-task logistic regression model is trained within the group of most similar cases identified by machine learning SVM for the case under investigation. Survival estimations are visualized by the Kaplan-Meier method, and significance is calculated by a log-rank test. The discriminative ability and the calibration of the individual survival prediction model was validated by the C-index, and the 1-calibration methods, respectively.
Results. Clinical data from all together 354,172 breast cancer cases were incorporated, and 51,206 cases from these had complete follow-up and treatment data. Twelve clusters with characteristic outcome and therapeutic response were identified. New cases were assigned into the closest cluster with an accuracy over 97.7%. The prediction model was well calibrated for 2-6 years from diagnosis at p<0.01, overestimating 5-year overall survival by 1.81%. The C-index values for the model’s discriminative capacity were 0.77 and 0.76 for five- and ten-year overall survival, respectively.
Conclusions. We have constructed a well-calibrated artificial-intelligence based survival prediction model suitable for different cohorts of breast cancer patients. The classification utilizes a limited set of available clinical and pathological variables enabling application in everyday clinical practice.

Keywords : Oncology, Personalized medicine, Clinical data

09:00 am – 10:00 am

SESSION VII

DIGITAL HEALTH

Chairs: Ekaterini Chatzaki, Alexandroupolis, Greece / Michael Marschler, Henstedt-Ulzburg, Germany

09:00 am – 09:30 am

Mobile Health (mHealth) and Internet of Things (IoT)

Alexander Haliassos, Athens, Greece

Mobile Health (mHealth) and Internet of Things (IoT)

Dr. Alexander Haliassos,
MD, PhD, EurSpLM ESEAP, the Greek Proficiency Testing Scheme for Clinical Laboratories. Athens, Grece.

When internet based enabling technologies are coupled with new capabilities in mobile communications providing remote access from everywhere using web enabled smart personal devices (phones, tablets and laptops) an opportunity is created that can revolutionize, not only the scope, but also the process healthcare. These technologies, that moreover require an extended data access and communication infrastructure enables biomedical personnel to access data, instruments, sensors, and expertise independent of their location.
mHealth (or m-health) is an abbreviation for mobile health, a term used for the practice of medicine and public health supported by mobile devices such as: mobile communication devices, mobile phones, tablets, PDAs, and wearable devices such as smart watches, for health services, information, and data collection, information exchange and communication via the Internet.
mHealth is one aspect of eHealth that is pushing the limits of how to acquire, transport, store, process, and secure the raw and processed data to deliver meaningful results.
mHealth applications include the use of mobile devices in collecting community and clinical health data, delivery of healthcare information to practitioners, researchers, and patients, real-time monitoring of patient vital signs, and direct provision of care (via mobile telemedicine).
mHealth started at the industrialized nations, but emerged in recent years as an application for developing countries, stemming from the rapid rise of mobile phone penetration in low-income nations where they face a plethora of constraints in their healthcare systems.
It provides greater access to larger segments of a population in developing countries, and improves the capacity of health systems in such countries to provide quality healthcare.
In  mHealth, projects operate with a variety of objectives:

  • increased access to healthcare and health-related information (in hard-to-reach populations),
  • improved ability to diagnose and track diseases,
  • timelier, more actionable public health information,
  • expanded access to medical education and training for health professionals.

But there are concerns about the accuracy & unregulated status of health apps.
The Internet of Things concept has three pillars for its development:
Connectivity: The universalization of Internet allows everyone to connect with high bandwidth through cellphones or wireless networks (WiFi).
Sensing Devices: Universalization of cheap devices with sensing capabilities. There are sensors for any of the five human senses. P.ex. smartphones can sense in which position they are, if the user is looking at them, if the user is speaking to them, how fast the user is moving and where in the world it is placed. Recently are in developpment more sophisticated sensors that can detectb smells and flavors.
Computational Power: Not only today’s devices (like smartphones, tablets) have the same computational power of IBM’s 80’s computers of the size of a room, but any device is able to access additional computational power through the Cloud and its virtual services.
The term “big data” tends to refer to the use of:

  • Predictive analytics,
  • User behavior analytics,
  • Other advanced data analytics methods that extract value from data.

Data sets grow rapidly mainly because they are increasingly gathered by cheap and numerous information-sensing Internet of things devices such as mobile devices, aerial and drones (remote sensing), software logs, web cameras, microphones, radio-frequency identification (RFID) tags and wireless sensor networks. In our domain the large quantity of anonymized data from laboratory results can be utilized, using the big data analysis methods in order to produce novel and useful information and help the improvement of the quality of service of Medical Laboratories, as also as the level of the provided healthcare services.
The digital divide describes the differences between those who have access to the Internet and those who do not because of economic reasons. It is describes also the lack of computer competency or self-efficacy and/or the lack of communications infrastructure. This situation can impact negatively the use of the above described technologies in many areas of our world. This can be partially compensated using specialized applications off-line on computers or mobile devices.

09:30 am – 10:00 am

AI in cancer, emergency and COVID-19

Ivan Brandslund, Odense, Denmark

AI in cancer, emergency and COVID-19

Ivan Brandslund, MD, DMSc, Professor
University of Southern Denmark

Background
AI is a promising technology to use in analysis of numerous data and in diagnostics as applied e.g. to evaluation of laboratory tests results
Based on the assumption that the effect of any disease would change the pattern of laboratory test results and thus a possibility that analysis of these patterns could evaluate absolute risk for specific diseases, we have tested the ability of AI to predict risk of cancer in patients consulting their general practitioner, the predictive values for sepsis, death and specific diseases in emergency received patients as well as analyzed consecutive data from patients admitted with severe disease caused by COVID-19.
Our results are that risk of cancer can be measured to between 0 and 80%, emergency received patients outcome predicted with area under the curve in ROC analysis of between 87% and 92% and that the analytical test with the highest predictive value for outcome in COVID-19 is the absolute concentration of virus particles in the blood at admittance.
We believe that AI will be a part of the clinical diagnostic methodologies within the next 10 years.
New projects are planned based on these promising results.

10:00 am – 10:30 am

COFFEE BREAK

10:30 am – 01:00 pm

SESSION VIII

PHARMACOGENOMICS AND POST-MARKETING APPLICATIONS

Charity Nofziger, Salzburg, Austria / Vangelis Manolopoulos, Alexandropoulis, Greece  

10:30 am – 11:00 am

Pharmacogenetics testing in a health care system: opportunities and challenges

Ron van Schaik, Rotterdam, The Netherlands

Pharmacogenetics testing in a health care system: opportunities and challenges 

Ron HN van Schaik
Professor of Pharmacogenetics, Dept. Clinical Chemistry, Erasmus MC, Rotterdam, The Netherlands

For the most effective use of pharmacogenetic testing, the uptake in a health care system is key. This stretches from easy and straightforward ways to ask for testing, easy sample collection, trustable, accurate and timely results, but also reporting and reimbursement issues. When in a country, several laboratories are performing the testing, harmonization of testing, interpretation and reporting become essential topics. In the Netherlands, we managed to implement much of this chain, including that every pharmacist in our country can provide genotype-based dosing advice for more than 100 drugs. To have the system operating, continuous education of specialist, GPs, pharmacists, students, patients and insurers was organized. One challenge still to be addressed in our country is the fact that genotype to phenotype interpretations may undergo change in time. It is important to have genotype portals, or national electronic health records available to notify already genotyped patients about any changes in interpretation. Although this brings another aspect forward: how does the patient react to this change of interpretation when he/she was treated based on the original reports? An interesting challenge we should discuss as a scientific community.

11:00 am – 11:15 am

Efforts of the Pharmacogene Variation Consortium (PharmVar) to facilitate the interpretation of pharmacogenetic test results and guide precision medicine

Charity Nofziger, Salzburg, Austria

Efforts of the Pharmacogene Variation Consortium (PharmVar) to facilitate the interpretation of pharmacogenetic test results and guide precision medicine

Charity Nofziger,
Lead PGx Analytics, PharmGenetix GmbH, Anif/Niederalm, Austria

The Pharmacogene Variation Consortium (PharmVar) is the home for pharmacogene nomenclature that serves as a centralized data repository for single nucleotide variants (SNVs) in PGx related genes. It’s main goal is to catalogue allelic variation in genes that play a role in the metabolism, disposition and response to drugs, and provide a unifying and standardized nomenclature system for the entire PGx community. In my presentation, I will give a quick overview of the website and highlight its main features, tools and resources to facilitate your PGx related work.

11:15 am – 11h30 am

Method for CYP2D6 Copy Number Variation Analysis using Multiplex Digital PCR on the QuantStudio Absolute Q System

Ferrier Le, San Francisco, Californie, USA

Method for CYP2D6 Copy Number Variation Analysis using Multiplex Digital PCR on the QuantStudio Absolute Q System

Ferrier Le,
Thermo Fisher Scientific

We developed a method using multiplex TaqMan® digital PCR to analyze CYP2D6 copy number variation using the QuantStudioTM Absolute QTM Digital PCR System. The system’s four optical channels enabled the development of a custom 4-plex digital PCR assay for the copy number variation analysis of three CYP2D6 regions (exon 9, intron 2, and 5’ UTR) in a single digital PCR reaction. The assay performance was verified using a panel of reference DNA samples. Compared to existing methods, our workflow using the Absolute Q system with the multiplex CYP2D6 assay reduced the time to results for copy number variation analysis without compromising accuracy and performance.

11:30 am – 12:00 pm

Pharmacogenomics of tyrosine kinase inhibitors

Ingolf Cascorbi, Kiel, Germany

Pharmacogenomics of tyrosine kinase inhibitor resistance

Ingolf Cascorbi,
Institute of Experimental and Clinical Pharmacology, University Hospital Schleswig-Holstein, 24105 Kiel, Germany.

Tyrosine kinase inhibitors (TKI) are widely used in the modern treatment of malignancies. Major success was achieved e.g. in the treatment of chronic myeloid leukemia (CML) through imatinib, inhibiting the catalytic domain of the BCR-ABL fusion gene product. However, resistances may be caused by BCR-ABL independent mechanisms. Our group identified mechanisms of drug resistance applying CML in-vitro models of imatinib as well as nilotinib resistance. We could demonstrate significant up-regulation of the ABCG2 efflux transporter strongly association to deregulation of specific miRNA. These mechanisms could be reversed however only under treatment-naive conditions. Further investigations revealed substantial changes of gene expression and (epi)genetics, related established oncogene signaling pathways but interestingly also to cell adhesion pathways. The talk will give a brief overview on mechanisms TKI resistance in vivo and in-vitro (Kaehler M and Cascorbi I. Pharmacogenomics of impaired tyrosine kinase inhibitor response: Lessons learned from chronic myelogenous leukemia. Front Pharmacol 2021;12:696960).

12:00 pm – 12:30 pm

Drug-Personal Interaction Network, a bioinformatic tool in the clinical routine: The Italian experience

Maurizio Simmaco, Roma, Italy

Drug-Personal Interaction Network, a bioinformatic tool in the clinical routine: The Italian experience

M Borro1,2, G Gentile1,2, O De Luca2, L Lionetto2, F Santamaria3, A Del Casale4, Maurizio Simmaco1,2
1Department of Neurosciences, Mental Health and Sensory Organs (NESMOS), Sapienza University, Via di Grottarossa 1035/1039, 00189 Rome, Italy, 2Laboratory of Clinical Biochemistry, Sant’Andrea  University Hospital, Via di Grottarossa 1035/1039, 00189 Rome, Italy, 3Clinical and Molecular Medicine Department, Sapienza University, Rome, Italy, 4Department of Dynamic and Clinical Psychology, and Health Studies, Faculty of Medicine and Psychology, Sapienza University, Rome; Unit of Psychiatry, ‘Sant’Andrea’ University Hospital, Via di Grottarossa 1035-1039, 00189 Rome, Italy

Background: The biological inter-individual variability in drug response is a multi-factorial phenomenon modified by both static factors, as the genomic make-up, and by dynamic factors, as ageing, lifestyle, environment. In addition, the concomitant use of many drugs (e.g. polypharmacy) presents the peculiar risk of drug-drug interactions (DDIs) which can alter drug’s pharmacokinetics (PKs) or pharmacodynamics (PDs), causing adverse effects and/or inefficacy.
Objective: The objective was to provide evaluation of the clinical utility of a novel Clinical Decision Support Systems (CDSS), named Drug-PIN, aimed to patient-sized drug selection.
Design: The study included 200 patients diagnosed with Major Depressive Disorders or a depressive episode in Bipolar Disorder, with at least three previous failed treatments, who underwent pharmacogenomic profiling and pharmacological counselling in the Sant’Andrea Hospital of Rome. The baseline poly-therapy of these patients were re-evaluated and optimized by Drug-PIN. The improvement of clinical outcome after Drug-PIN therapy optimization was evaluated by the HAM-D scale, a structured questionnaire broadly used to evaluate the severity of depression.
Results: Drug-PIN poly-therapy optimization causes a significant improvement of the clinical outcome, as shown by the statistically significant decrease in the HAM-D scale score.
Conclusions: Application of automated tools for therapy design according to patient-specific characteristics, including personal genomic profile, improve therapy safety and efficacy. Notably, the automation of pharmacological counselling allows to deliver precision medicine to a huge number of patients compared to non-automated procedures.
Reference: 1. Borro M et al. Pharmgenomics Pers Med. 2021 Aug 5;14:955-962. doi: 10.2147/PGPM.S316556.

12:30 pm – 01:00 pm

Precision Medicine in Routine Turkish Clinical Practice: Now and in the Future

Belgin Süsleyici, Istanbul, Turkey

Precision Medicine in Routine Turkish Clinical Practice: Now and in the Future

Belgin Süsleyici Profesor, PhD
Marmara University, Faculty of Sciences and Letters, Department of Molecular Biology, Istanbul, Turkey

In recent years, traditional treatment plans have been augmented by precision medicine approaches. However, there are still significant issues to be overcome in incorporating these approaches into routine care and integrating new research data to clinical practice. With this awareness, we began large-scale strategic projects carried out with the collaboration of many clinicians and scientists, and with significant support of the Ministry of Health in Turkey.
We started our studies by performing pharmacogenetic analyses according to the drug-use status of patients from cardiology, oncology, psychiatry as well as physical therapy and rehabilitation clinics. The effects of CYP2C9 and VKORC1 polymorphisms on warfarin-dose requirements in Turkish patients were determined and as a conclusion to the CYP2C9 *2, *3, VKORC1 9041 G>A polymorphisms were found to explain the considerable proportion of inter-individual variability in warfarin dose requirement.
The carrier frequencies of CYP2C19 gene polymorphisms affecting the CYP2C19 enzyme activity in Turkish patients are routinely getting to be prescribed clopidogrel and proton pump inhibitors to predict the efficiency and possible drug related risks before the initiation of treatment.  As our results demonstrated, the individualized metoprolol doses to be used in treatment of heart rates and blood pressures for cardiac patients and tramadol responses for physical therapy and rehabilitation patients were related to CYP2D6 genotyping, pharmacogenetic results of CYP2C6 are being considered before drug prescriptions.
In oncology, the relationships between 5-FU treatment-related adverse events and DPYD, MTHFR and TYMS gene polymorphisms involved in 5-FU metabolism in colorectal cancer (CRC) patients were evaluated. Together with genes affecting 5-FU response, the relationship between bevacizumab use and specific VEGF polymorphisms, have been investigated based on the survival time and metastasis in colorectal cancer patients. To be used in novel immunotherapies and chemotherapies PD-1 and PDL-1 polymorphisms are newly started to be used to foresee individualized cancer prognosis, overall survival, progression-free survival and response to drugs.   The results obtained from the PDL-1 checkpoint inhibitor have been used to produce a real time PCR kit and has been started to be used to help clinicians determine the  immunotherapeutics they will be using in targeted therapies.
According to the experiences and collaborations from our past research, we are continuing with further studies with new genes available which seem to have potential in individualized drug response that we believe will provide new data in both the implementation of precision medicine in Turkish clinical practice and to the improvement of existing treatment regimens. Since we assume that the variations in endothelial-mesenchyme transformation inducers like SNAI1 and LOXL2, may have synchronous effect on metastases resulting with malignant phenotype, genotyping results are being recorded for these gene polymorphisms for their clarification to be used in PGx routine. We believe that the data being collected in the Turkish population will contribute in understanding both malignancy and the potential of new therapeutic targets to be used in the treatment processes of various disease.

01:00 pm – 01:15 pm

CLOSING SESSION

Sofia Siest, Nancy, France