Example Of Precision Medicine Research Articles

Precision Medicine-Are We There Yet? A Narrative Review of Precision Medicine's Applicability in Primary Care.

Precision medicine (PM), also termed stratified, individualised, targeted, or personalised medicine, embraces a rapidly expanding area of research, knowledge, and practice. It brings together two emerging health technologies to deliver better individualised care: the many "-omics" arising from increased capacity to understand the human genome and "big data" and data analytics, including artificial intelligence (AI). PM has the potential to transform an individual's health, moving from population-based disease prevention to more personalised management. There is however a tension between the two, with a real risk that this will exacerbate health inequalities and divert funds and attention from basic healthcare requirements leading to worse health outcomes for many. All areas of medicine should consider how this will affect their practice, with PM now strongly encouraged and supported by government initiatives and research funding. In this review, we discuss examples of PM in current practice and its emerging applications in primary care, such as clinical prediction tools that incorporate genomic markers and pharmacogenomic testing. We look towards potential future applications and consider some key questions for PM, including evidence of its real-world impact, its affordability, the risk of exacerbating health inequalities, and the computational and storage challenges of applying PM technologies at scale.

Economic assessment of NGS testing workflow for NSCLC in a healthcare setting

BackgroundThe molecular diagnostic and therapeutic pathway of Non-Small Cell Lung Cancer (NSCLC) stands as a successful example of precision medicine. The scarcity of material and the increasing number of biomarkers to be tested have prompted the routine application of next-generation-sequencing (NGS) techniques. Despite its undeniable advantages, NGS involves high costs that may impede its broad adoption in laboratories. This study aims to assess the detailed costs linked to the integration of NGS diagnostics in NSCLC to comprehend their financial impact. Materials and methodsThe retrospective analysis encompasses 210 cases of early and advanced stages NSCLC, analyzed with NGS and collected at the IRCCS San Gerardo dei Tintori Foundation (Monza, Italy). Molecular analyses were conducted on FFPE samples, with an hotspot panel capable of detecting DNA and RNA variants in 50 clinically relevant genes. The economic analysis employed a full-cost approach, encompassing direct and indirect costs, overheads, VAT (Value Added Tax). ResultsWe estimate a comprehensive cost for each sample of €1048.32. This cost represents a crucial investment in terms of NSCLC patients survival, despite constituting only around 1% of the expenses incurred in their molecular diagnostic and therapeutic pathway. ConclusionsThe cost comparison between NGS test and the notably higher therapeutic costs highlights that the diagnostic phase is not the limiting economic factor. Developing NGS facilities structured in pathology networks may ensure appropriate technical expertise and efficient workflows.

Symptomatic Response to Antibiotics in Patients With Small Intestinal Bacterial Overgrowth: A Systematic Review and Meta-analysis.

We performed a systematic review and meta-analysis evaluating the symptomatic response rate to antibiotics in patients with small intestinal bacterial overgrowth (SIBO). Similarly, we performed a meta-analysis on the symptomatic response to antibiotics in irritable bowel syndrome (IBS) patients with and without SIBO. MEDLINE, EMBASE, Web of Science, and Cochrane databases were searched from inception to March 2021. Randomized controlled trials and prospective studies reporting dichotomous outcomes were included. There were 6 studies included in the first meta-analysis comparing the efficacy of antibiotics to placebo or no antibiotic. This included 196 patients, of whom 101 received antibiotics and 95 received placebo or no antibiotics. Significantly more patients improved with antibiotics (relative risk [95% CI] = 2.46 [1.33-4.55], P = 0.004). There were 4 studies included in the analysis comparing symptomatic response rates in IBS patients with or without SIBO with 266 IBS patients, of whom 172 had SIBO and 94 did not. The pooled response rate for symptomatic response was 51.2% in the SIBO group vs 23.4% in the no SIBO group, respectively. Significantly more IBS patients with SIBO responded to antibiotics compared to those without SIBO (relative risk [95% CI] = 2.07 [1.40-3.08], P = 0.0003). Antibiotics appear to be efficacious in treating SIBO, although small sample sizes and poor data quality limit this interpretation. Symptomatic response rates also appear to be higher in IBS patients with SIBO. This may be the first example of precision medicine in IBS as opposed to our current empiric treatment approach. Large-multicenter studies are needed to verify the results.

Dual inhibition of EZH2 and G9A/GLP histone methyltransferases by HKMTI-1-005 promotes differentiation of acute myeloid leukemia cells.

All-trans-retinoic acid (ATRA)-based differentiation therapy of acute promyelocytic leukemia (APL) represents one of the most clinically effective examples of precision medicine and the first example of targeted oncoprotein degradation. The success of ATRA in APL, however, remains to be translated to non-APL acute myeloid leukemia (AML). We previously showed that aberrant histone modifications, including histone H3 lysine 4 (H3K4) and lysine 27 (H3K27) methylation, were associated with this lack of response and that epigenetic therapy with small molecule inhibitors of the H3K4 demethylase LSD1/KDM1A could reprogram AML cells to respond to ATRA. Serving as the enzymatic component of Polycomb Repressive Complex 2, EZH2/KMT6A methyltransferase plays a critical role in normal hematopoiesis by affecting the balance between self-renewal and differentiation. The canonical function of EZH2 is methylation of H3K27, although important non-canonical roles have recently been described. EZH2 mutation or deregulated expression has been conclusively demonstrated in the pathogenesis of AML and response to treatment, thus making it an attractive therapeutic target. In this study, we therefore investigated whether inhibition of EZH2 might also improve the response of non-APL AML cells to ATRA-based therapy. We focused on GSK-343, a pyridone-containing S-adenosyl-L-methionine cofactor-competitive EZH2 inhibitor that is representative of its class, and HKMTI-1-005, a substrate-competitive dual inhibitor targeting EZH2 and the closely related G9A/GLP H3K9 methyltransferases. We found that treatment with HKMTI-1-005 phenocopied EZH2 knockdown and was more effective in inducing differentiation than GSK-343, despite the efficacy of GSK-343 in terms of abolishing H3K27 trimethylation. Furthermore, transcriptomic analysis revealed that in contrast to treatment with GSK-343, HKMTI-1-005 upregulated the expression of differentiation pathway genes with and without ATRA, while downregulating genes associated with a hematopoietic stem cell phenotype. These results pointed to a non-canonical role for EZH2, which was supported by the finding that EZH2 associates with the master regulator of myeloid differentiation, RARα, in an ATRA-dependent manner that was enhanced by HKMTI-1-005, possibly playing a role in co-regulator complex exchange during transcriptional activation. In summary, our results strongly suggest that addition of HKMTI-1-005 to ATRA is a new therapeutic approach against AML that warrants further investigation.

18F-Fluoroestradiol: Current Applications and Future Directions

In the United States, breast cancer is the second leading cause of cancer death in all women and the leading cause of cancer death in Black women. The breast cancer receptor profile, assessed with immunohistochemical staining of tissue samples, allows prediction of outcomes and direction of patient treatment. Approximately 80% of newly diagnosed breast cancers are hormone receptor (HR) positive, which is defined as estrogen receptor (ER) and/or progesterone receptor (PR) positive. Patients with ER-positive disease can be treated with therapies targeting the ER; however, the assessment of ER expression with immunohistochemical staining of biopsy specimens has several limitations including sampling error, false-negative results, challenging or inaccessible biopsy sites, and the inability to synchronously and serially assess all metastatic sites to identify spatial and/or temporal ER heterogeneity. In May 2020, after decades of research, the U.S. Food and Drug Administration approved the PET radiotracer fluorine 18 (18F) fluoroestradiol (FES) for clinical use in patients with ER-positive recurrent or metastatic breast cancer as an adjunct to biopsy. FES binds to the ER in the nucleus of ER-expressing cells, enabling whole-body in vivo assessment of ER expression. This article is focused on the approved uses of FES in the United States, including identification of a target lesion for confirmatory biopsy, in vivo assessment of biopsy-proven ER-positive disease, and evaluation of spatial and temporal ER heterogeneity. FES is an example of precision medicine that has been leveraged to optimize the care of patients with breast cancer. © RSNA, 2023 See the invited commentary by Fowler in this issue. Quiz questions for this article are available through the Online Learning Center.

Immunotherapy in Cancer: Biology Therapy

Abstract: 
 The relationship between immune system and cancer has progressively increased in the last few years. Recent advancement in treating cancer immunotherapy includes monoclonal antibodies, adaptive cancer therapy; monoclonal antibodies have came into force. General therapies include surgery, radiation and chemotherapy etc... Beyond that the immunotherapy in treating cancer helps our immune system to fight against tumor forming cell, which acts as an example of precision medicine .It mainly targets tumor in filtering lymphocytes, CAR Tcells, TCR Tcell etc…. Personalized combination therapy stands as promising stratergy for upcoming cancer treatment, personalized medicines includes patient derived tumor cell DNA oncolytic viruses dendritic cells etc.

Getting it right first time – precision medicine in diabetes

Abstract Precision medicine – ‘The right therapy for the right patient at the right time – every time’ – has been a hot topic over the past few years. The definition refers not just to treatment but also to diagnosis, prevention and prognosis. The evidence base for precision medicine is drawn from three categories: (i) assessment of the genetic and metabolic state; (ii) interrogation of big data to inform disease categories; (iii) science‐guided preventative and treatment decisions.The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) launched the Precision Medicine in Diabetes Initiative (PMDI) in 2018. Their first consensus report was published in 2020, with a four‐phase plan in place to produce guidelines and commence education of clinicians and patients by 2025.The best example of precision medicine in diabetes is monogenic diabetes, for which a genetic test in an individual identifies a specific diabetes type with implications for treatment. At the other extreme, ADA/EASD guidelines for type 2 diabetes identify four broad groups (cardiovascular disease risk; risk of hypoglycaemia; weight; cost) to guide treatment choice. Data analysis has led to identification of clusters within type 2 diabetes, with different clinical and genetic characteristics, but simple clinical factors such as age, weight, and eGFR may be sufficient to predict therapeutic response.For precision medicine to benefit the millions of people with diabetes globally, characteristics used to identify the best treatment for subgroups of populations must be easily measured and inexpensive. Precision medicine is a tool to aid treatment selection but the final choice must lie with the person who will be taking the treatment. Copyright © 2022 John Wiley & Sons.

Precision Medicine and Sickle Cell Disease.

Sickle cell disease (SCD) is characterized by variable clinical outcomes, with some patients suffering life-threatening complications during childhood, and others living relatively symptom-free into old age. Because of this variability, there is an important potential role for precision medicine, in which particular different treatments are selected for different groups of patients. However, the application of precision medicine in SCD is limited by difficulties in identifying different prognostic groups and the small number of available treatments. The main genetic determinant of outcomes in SCD is the underlying β-globin genotype, with sickle cell anemia (HbSS) and hemoglobin SC disease (HbSC) forming the 2 major forms of the disease in most populations of African origin. Although there are clear differences in clinical outcomes between these conditions, treatments approaches are very similar, with little evidence on how to treat HbSC in particular. Other genomic information, such as the co-inheritance of α-thalassemia, or high fetal hemoglobin (HbF) levels, is of some prognostic value but insufficient to determine treatments. Precision medicine is further limited by the fact that the 2 main drugs used in SCD, penicillin and hydroxyurea, are currently recommended for all patients. Newer treatments, such as crizanlizumab and voxelotor, raise the possibility that groups will emerge who respond best to particular drugs or combinations. Perhaps the best current example of precision medicine in SCD is the selective use of blood transfusions as primary stroke prevention in children with evidence of cerebral vasculopathy. More precise treatments may emerge as we understand more about the pathology of SCD, including problems with erythropoiesis.

Comparison of Four Machine Learning Techniques for Prediction of Intensive Care Unit Length of Stay in Heart Transplantation Patients.

BackgroundPost-operative heart transplantation patients often require admission to an intensive care unit (ICU). Early prediction of the ICU length of stay (ICU-LOS) of these patients is of great significance and can guide treatment while reducing the mortality rate among patients. However, conventional linear models have tended to perform worse than non-linear models.Materials and MethodsWe collected the clinical data of 365 patients from Wuhan Union Hospital who underwent heart transplantation surgery between April 2017 and August 2020. The patients were randomly divided into training data (N = 256) and test data (N = 109) groups. 84 clinical features were collected for each patient. Features were validated using the Least Absolute Shrinkage and Selection Operator (LASSO) regression’s fivefold cross-validation method. We obtained Shapley Additive explanations (SHAP) values by executing package “shap” to interpret model predictions. Four machine learning models and logistic regression algorithms were developed. The area under the receiver operating characteristic curve (AUC-ROC) was used to compare the prediction performance of different models. Finally, for the convenience of clinicians, an online web-server was established and can be freely accessed via the website https://wuhanunion.shinyapps.io/PredictICUStay/.ResultsIn this study, 365 consecutive patients undergoing heart transplantation surgery for moderate (NYHA grade 3) or severe (NYHA grade 4) heart failure were collected in Wuhan Union Hospital from 2017 to 2020. The median age of the recipient patients was 47.2 years, while the median age of the donors was 35.58 years. 330 (90.4%) of the donor patients were men, and the average surgery duration was 260.06 min. Among this cohort, 47 (12.9%) had renal complications, 25 (6.8%) had hepatic complications, 11 (3%) had undergone chest re-exploration and 19 (5.2%) had undergone extracorporeal membrane oxygenation (ECMO). The following six important clinical features were selected using LASSO regression, and according to the result of SHAP, the rank of importance was (1) the use of extracorporeal membrane oxygenation (ECMO); (2) donor age; (3) the use of an intra-aortic balloon pump (IABP); (4) length of surgery; (5) high creatinine (Cr); and (6) the use of continuous renal replacement therapy (CRRT). The eXtreme Gradient Boosting (XGBoost) algorithm presented significantly better predictive performance (AUC-ROC = 0.88) than other models [Accuracy: 0.87; sensitivity: 0.98; specificity: 0.51; positive predictive value (PPV): 0.86; negative predictive value (NPV): 0.93].ConclusionUsing the XGBoost classifier with heart transplantation patients can provide an accurate prediction of ICU-LOS, which will not only improve the accuracy of clinical decision-making but also contribute to the allocation and management of medical resources; it is also a real-world example of precision medicine in hospitals.

Dravet Syndrome as an Example of Precision Medicine in Epilepsy.

Dravet syndrome (DS) is a drug-resistant, early-onset, developmental and epileptic encephalopathy where there have been many recently approved therapies with many more in development. With the availability of more syndrome specific treatment options coupled with an earlier diagnosis, DS is well-positioned to be an example of how a precise syndromic diagnosis can guide treatment choices and improve overall outcomes and also allow for the development of potential disease modifying therapies to address more than just seizures. In this review we summarize the current state of DS approved therapies and those that are in various stages of development.

Precision Medicine Based on CFTR Genotype for People with Cystic Fibrosis.

Cystic fibrosis (CF) is an autosomal recessive genetic condition that is caused by variants in the cystic fibrosis transmembrane conductance regulator gene. This causes multisystem disease due to dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel at the apical surface of epithelia. Until recently, treatment was directed at managing the downstream effects in affected organs, principally improving airway clearance and treating infection in the lungs and improving malabsorption in the gastrointestinal tract. Care delivered by multidisciplinary teams has yielded incremental improvements in outcomes. However, the development of small-molecule CFTR modulator drugs over the last decade has heralded a new era of CF therapeutics. Modulators target the underlying defect and improve CFTR function. Either monotherapy or a combination of modulators is used depending on the specific genotype and class of CFTR disease-causing variants that an individual has. Both ivacaftor and the ivacaftor/tezacaftor/elexacaftor combination have been demonstrated to be associated with clinically very significant benefits in randomised trials and have rapidly been made available as part of standard care in many countries. CFTR modulators represent one of the best examples of precision medicine to date. They are expensive, however, and equity of access to them worldwide remains an issue. Studies and approvals are also ongoing for children under the age of 6 years for ivacaftor/tezacaftor/elexacaftor. Furthermore, no modulators are available for around 10% of the people with CF. In this review, we firstly summarise the genetics, pathophysiology and clinical problems associated with CF. We then discuss the development of CFTR modulators and key clinical trials to support their use along with other potential future therapeutic approaches.

Quantifying the Impact of Capacity Constraints in Economic Evaluations: An Application in Precision Medicine.

BackgroundExamples of precision medicine are complex interventions featuring both testing and treatment components. Because of this complexity, there are often barriers to the introduction of such interventions. Few economic evaluations attempt to determine the impact of these barriers on the cost-effectiveness of the intervention. This study presents a case study economic evaluation that illustrates how the value of implementation methods may be used to quantify the impact of capacity constraints in a decision-analytic model.MethodsA baseline decision-analytic model-based economic evaluation of ALK mutation testing was reproduced from a published technology appraisal. Three constraints (commissioning awareness, localization of testing, and pathology laboratory capacity) were identified using qualitative interviews, parameterized, and incorporated into the model. Value of implementation methods were used alongside incremental cost-effectiveness ratios (ICERs) to quantify the impact on the cost-effectiveness and net monetary benefit (NMB) of each capacity constraint and from the 3 constraints combined.ResultsEach of the 3 capacity constraints resulted in a loss of NMB ranging from £7773 (0.1% of the total) per year for localized testing to £4,907,893 (77%) for a lack of awareness about commissioning ALK testing. When combined, the constraints resulted in a loss of NMB of £5,289,414 (83%). The localization and limited pathology capacity constraints slightly increased the ICER, but the lack of commissioning awareness constraint did not change the ICER.ConclusionsCapacity constraints may have a significant impact on the NMB produced by examples of precision medicine. Value of implementation methods can be used to quantify the impact of such constraints by combining the impact of the constraints on the cost-effectiveness of the intervention with the impact on the number of patients receiving the intervention.HighlightsWhile capacity constraints may prevent the use of precision medicine in clinical practice, economic evaluations rarely account for the impact of such barriers.This study demonstrates how constraints can be identified using qualitative methods and subsequently incorporated into decision-analytic models using quantitative value of implementation methods.In addition, this article demonstrates how value of implementation methods can be used to account for the impact of capacity constraints on the costs and benefits of an intervention as well as the number of patients receiving the intervention.In the case study presented herein, a capacity constraint reducing patient access to an example of precision medicine caused the biggest loss of net monetary benefit.Health economists should consider moving beyond incremental cost-effectiveness ratios to measures of total net monetary benefit to fully capture the impact of implementing precision medicine.

Attualità in nefrologia pediatrica: le conoscenze di rilievo per il nefrologo dell’adulto

Examples of innovative research in pediatric nephrology include: a) the typically pediatric field of Congenital Anomalies of the Kidney and Urinary Tract (CAKUT), which has benefited from the discovery of numerous gene mutations responsible for the various malformations and the demonstration of the congenital origin of most of the renal damage, resulting in a decrease of invasive imaging, antibiotic prophylaxis and surgery;
 b) the approach to glomerular diseases that appear in childhood, like idiopathic nephrotic syndrome (INS), IgA nephropathy (IgAN) and C3 glomerulopathies (C3G).
 B and T lymphocyte disregulations and molecular podocyte alterations of immunological and genetic origin have been described in INS as main determinants of proteinuria. In IgAN, the discovery of an abnormal IgA glycosilation in the mucosal B cells has driven to new trials with Budesonide and Sparsentan and to innovative therapies, like atacicept. A new classification of C3G has been proposed after the description of genetic mutations of factors inhibiting activation of the alternative complement pathway, and monoclonal anti-C5 antibody Eculizumab has consequently entered the therapeutic armamentarium;
 c) the initial attempts at gene therapy, with promising results obtained in Alport syndrome, nephropathic cystinosis and Dent syndrome.
 Moreover, a clear example of precision medicine is represented by the refinement of the dosage of Eculizumab in the treatment of atypical HUS, while slow-medicine recommendations exist for common clinical conditions, like urinary tract infections, microscopic hematuria and proteinuria.

Understanding barriers to the introduction of precision medicine in non-small cell lung cancer: a qualitative interview study

Background: While treatments targeting genetic mutations and alterations in non-small cell lung cancer (NSCLC) have been available since 2010, the adoption of such examples of precision medicine into clinical practice has historically been slow. This means that patients with NSCLC may not have received life improving and extending treatments which should have been available to them. The purpose of this qualitative interview study was to identify the barriers to the provision of examples of precision medicine for NSCLC. Methods: This study used semi-structured telephone interviews with clinicians, test providers and service commissioners to identify the perceived barriers to providing historical, current, and future examples of precision medicine in NSCLC. Participants were identified through mailing list advertisements and snowball sampling. The qualitative data was analysed using a framework analysis. Results: Interviews were conducted with 11 participants including: five oncologists; three pathologists; two clinical geneticists; and one service commissioner. A total of 17 barriers to the introduction of precision medicine for NSCLC were identified and these were grouped into five themes: the regulation of precision medicine and tests; the commissioning and reimbursement of tests and the testing process; the complexity of the logistics around providing tests; centralisation or localisation of test provision; and opinions about future developments in precision medicine for NSCLC. Conclusions: A number of barriers exist to the introduction of precision medicine in NSCLC. Addressing these barriers may improve access to novel life improving and extending treatments for patients.

ARIA 2019: An Integrated Care Pathway for Allergic Rhinitis in Portugal

The Allergic Rhinitis and Its Impact on Asthma (ARIA) initiative started more than 20 years ago and has developed and disseminated evidence-based guidelines and projects in the field of allergic rhinitis. This initiative is currently focused on providing patient-centred guidelines that contribute to an integrated care pathway between the various levels of care and take advantage of digital solutions, and the introduction of integrated care pathways in clinical practice has been recommended. In this article we describe the adaptation for Portugal of the ARIA Integrated Care Pathways document. After a brief review of the epidemiology and impact of allergic rhinitis in Portugal and the activities carried out in Portugal within the ARIA initiative, we describe the broad knowledge base used for the development of recommendations for the pharmacological treatment of allergic rhinitis, and these recommendations are based on the GRADE methodology, real world evidence acquired by mobile technology (mHealth) and resulting from allergenic exposure chamber studies. What follows is a summary of integrated care pathways for allergen immunotherapy produced in 2019. Allergen immunotherapy is considered an example of precision medicine where the use of mHealth technologies will improve stratification for patient selection and response monitoring. These recommendations were considered as best practices of integrated patient-centred care supported by digital systems from Directorate General for Health and Food Safety of the European Union (DG Santé) and represent the ARIA Phase 4 Change Management strategy.

5P Strategies for Management of Multiple Endocrine Neoplasia Type 2: A Paradigm of Precision Medicine.

Multiple endocrine neoplasia type 2 (MEN2) is a neuroendocrine cancer syndrome characterized by medullary thyroid carcinoma, in combination or not with pheochromocytoma, hyperparathyroidism, and extra-endocrine features. MEN2 syndrome includes two clinically distinct forms subtyped as MEN2A and MEN2B. Nearly all MEN2 cases are caused by germline mutations of the RET proto-oncogene. In this review, we propose “5P” strategies for management of MEN2: prevention, prediction, personalization, psychological support, and participation, which could effectively improve clinical outcomes of patients. Based on RET mutations, MEN2 could be prevented through prenatal diagnosis or preimplantation genetic testing. Identification of pathogenic mutations in RET can enable early diagnosis of MEN2. Combining RET mutation testing with measurement of serum calcitonin, plasma or urinary metanephrine/normetanephrine, and serum parathyroid hormone levels could allow risk stratification and accurately prediction of MEN2 progression, thus facilitating implementation of personalized precision treatments to increase disease-free survival and overall survival. Furthermore, increased awareness of MEN2 is needed, which requires participation of physicians, patients, family members, and related organizations. Psychological support is also important for patients with MEN2 to promote comprehensive management of MEN2 symptoms. The “5P” strategies for management of MEN2 represent a typical clinical example of precision medicine. These strategies could effectively improve the health of MEN2 patient, and avoid adverse outcomes, including death and major morbidity, from MEN2.

Points to consider for reporting of germline variation in patients undergoing tumor testing: a statement of the American College of Medical Genetics and Genomics (ACMG)

The sequencing of tumor-derived DNA to identify tumor-specific variations (biomarkers) with potential diagnostic, prognostic, or predictive therapeutic implications (hereafter, “tumor testing”) is a prominent example of precision medicine. Although the primary goal of this testing is the identification of biomarkers to guide patient management, testing tumor genomes also has the potential to uncover clinically relevant germline variation that is associated with heritable cancer susceptibility and other conditions, and carrier status for autosomal recessive disorders, if confirmed to be present in the germline.

Usage Pattern of Carbamazepine and Associated Severe Cutaneous Adverse Reactions in Singapore Following Implementation of HLA-B*15:02 Genotyping as Standard-of-Care.

In April 2013, the Ministry of Health and Health Sciences Authority of Singapore jointly issued recommendations for HLA-B*15:02 genotyping before starting carbamazepine (CBZ) in new patients of Asian ancestry as standard of care. The Ministry of Health also approved a 75% subsidy for HLA-B*15:02 genotyping to all patients on subsidy at public healthcare institutions. To understand the impact of these regulatory decisions, we researched the usage patterns for CBZ and levetiracetam, the trend of Stevens–Johnson syndrome/toxic epidermal necrolysis [Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN)] reports associated with antiepileptic drugs and the take-up rates of HLA-B*15:02 tests in Singapore. In the 5-year post-policy period, we found that the annual number of reported SJS/TEN cases associated with all antiepileptic drugs was significantly decreased by 57% (p = 0.015); SJS/TEN cases associated with CBZ and phenytoin reduced by 92% and 42% respectively. New CBZ users decreased by 31% while new levetiracetam users approximately doubled. The annual number of HLA-B*15:02 tests conducted increased from 444 to approximately 1,200. Regulatory recommendations for HLA-B*15:02 genotyping as standard of care coupled with government subsidy for the test had contributed to a reduction in CBZ SJS/TEN in Singapore by >90%, in line with that observed in other Asian countries with similar policies. Additionally, the number of phenytoin-SJS/TEN cases also declined. Taken together, this represents a successful example of precision medicine through implementation of a genotyping program to reduce a rare but serious adverse drug reaction among at-risk individuals, while preserving the availability of an effective and low-cost medicine for the broader population.

Myocardial infarction with non-obstructive coronary arteries: what is the prognosis?

Myocardial infarction in the absence of obstructive coronary stenosis (MINOCA) is a syndrome with several causes, characterized by clinical evidence of myocardial infarction and coronary angiographically normal or almost normal (stenosis ≤50%). MINOCAs represent about 10% of acute coronary syndromes. The causes of MINOCA are manifold and can be classified on the basis of the mechanism in epicardial (unstable plaque not manifested by angiography, epicardial spasm and coronary dissection) or microvascular. The latter in turn can be divided into intrinsic (microvascular spasm, Takotsubo syndrome and coronary embolization) and extrinsic (myocarditis). In the former, the dysfunctional microcirculation causes myocardial necrosis due to reduction of the lumen due to vasoconstriction and / or obstruction, while in the latter, the compression of the lumen occurs ab extrinsic due to myocardial edema. Note that the prognosis of MINOCA is extremely variable and depends on the underlying cause with high risk clinical subsets. A correct diagnostic procedure includes first level tests (clinical / anamnestic examination, ECG, myocardial necrosis enzyme dosage, trans-thoracic echocardiogram, coronary angiography, ventriculogram) and second level tests (intracoronary imaging, coronary vasomotor test, cardiac nuclear magnetic resonance and trans-esophageal or contrast ultrasound). Through this process, it is possible to identify the cause of MINOCA, fundamental for targeting therapy on the disease mechanism, thus constituting a typical example of precision medicine.

PARP and PARG inhibitors in cancer treatment.

Oxidative and replication stress underlie genomic instability of cancer cells. Amplifying genomic instability through radiotherapy and chemotherapy has been a powerful but nonselective means of killing cancer cells. Precision medicine has revolutionized cancer therapy by putting forth the concept of selective targeting of cancer cells. Poly(ADP-ribose) polymerase (PARP) inhibitors represent a successful example of precision medicine as the first drugs targeting DNA damage response to have entered the clinic. PARP inhibitors act through synthetic lethality with mutations in DNA repair genes and were approved for the treatment of BRCA mutated ovarian and breast cancer. PARP inhibitors destabilize replication forks through PARP DNA entrapment and induce cell death through replication stress-induced mitotic catastrophe. Inhibitors of poly(ADP-ribose) glycohydrolase (PARG) exploit and exacerbate replication deficiencies of cancer cells and may complement PARP inhibitors in targeting a broad range of cancer types with different sources of genomic instability. Here I provide an overview of the molecular mechanisms and cellular consequences of PARP and PARG inhibition. I highlight clinical performance of four PARP inhibitors used in cancer therapy (olaparib, rucaparib, niraparib, and talazoparib) and discuss the predictive biomarkers of inhibitor sensitivity, mechanisms of resistance as well as the means of overcoming them through combination therapy.