Pediatric Acute Lymphoblastic Leukemia, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

J Natl Compr Canc Netw. 2020 Jan;18(1):81-112

Authors: Brown P, Inaba H, Annesley C, Beck J, Colace S, Dallas M, DeSantes K, Kelly K, Kitko C, Lacayo N, Larrier N, Maese L, Mahadeo K, Nanda R, Nardi V, Rodriguez V, Rossoff J, Schuettpelz L, Silverman L, Sun J, Sun W, Teachey D, Wong V, Yanik G, Johnson-Chilla A, Ogba N

Abstract
Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. Advancements in technology that enhance our understanding of the biology of the disease, risk-adapted therapy, and enhanced supportive care have contributed to improved survival rates. However, additional clinical management is needed to improve outcomes for patients classified as high risk at presentation (eg, T-ALL, infant ALL) and who experience relapse. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for pediatric ALL provide recommendations on the workup, diagnostic evaluation, and treatment of the disease, including guidance on supportive care, hematopoietic stem cell transplantation, and pharmacogenomics. This portion of the NCCN Guidelines focuses on the frontline and relapsed/refractory management of pediatric ALL.

PMID: 31910389 [PubMed - in process]

A Scoping Review of the Evidence Behind CYP2D6 Inhibitor Classifications.

Clin Pharmacol Ther. 2020 Jan 07;:

Authors: Cicali EJ, Smith DM, Duong BQ, Kovar LG, Cavallari LH, Johnson JA

Abstract
The FDA lists 22 medications as clinical inhibitors of CYP2D6, with classifications of strong, moderate, and weak. It is accepted that strong inhibitors result in nearly null enzymatic activity, but reduction caused by moderate and weak inhibitors is less well characterized. The objective was to identify if the classification of currently listed FDA moderate and weak inhibitors is supported by publicly available primary literature. We conducted a literature search and reviewed product labels (PLs) for AUC-fold changes caused by inhibitors in humans and identified 89 inhibitor-substrate pairs. Observed AUC-fold change of the substrate was used to create an observed inhibitor classification per FDA-defined AUC-fold change thresholds. We then compared the observed inhibitor classification with the classification listed in the FDA Table of Inhibitors. We found 62% of the inhibitors within the pairs matched the listed FDA classification. We explored reasons for discordance and suggest modifications to the FDA table of clinical inhibitors for cimetidine, desvenlafaxine, and fluvoxamine.

PMID: 31910286 [PubMed - as supplied by publisher]

Prevalence of overweight and obesity in children with X-linked hypophosphatemia.

Endocr Connect. 2020 Jan 01;:

Authors: Zhukouskaya V, Rothenbuhler A, Colao AA, Di Somma C, Kamenický P, Trabado S, Prie D, Audrain C, Barosi A, Kyheng C, Lambert AS, Linglart A

Abstract
BACKGROUND/AIM: X-linked hypophosphatemia (XLH) is a rare disease characterized by low phosphate levels. Scientific evidence points to link between hypophosphatemia and obesity in general population. The aim of our longitudinal observational study was to investigate the prevalence of obesity and associated factors in a large cohort of children with XLH.
PATIENTS/METHODS: We studied 172 XLH-children 5-20 years of age (113 girls /59 boys). Anthropometric parameters (weight, height, BMI) were collected at birth and during follow-up at mean ages of 5.3-8.2-11.3-15.9 years (groups 1-2-3-4, respectively). In each group, subjects were classified based on International Obesity Taskforce (IOTF) cut off values of BMI for age and sex as overweight or obese (IOTF 25-30 or ≥30 kg/m2, respectively).
RESULTS: In each age-group, almost 1/3 of XLH-patients were classified as overweight or obese (29.4%, 28.7%, 27.5% and 36.7% in groups 1-2-3-4, respectively). Children without a XLH-family history had higher BMI-IOTF at every point of follow-up, compared to those with positive XLH-family history. Similarly, higher BMI-IOTF was significantly associated with treatment duration (23.3±4.4 vs 23.8±3.8 vs 25.2±4.5 kg/m2, for subjects with treatment duration of <5, 5-10 and >10 years, respectively, p for trend=0.025). Multiple regression analysis confirmed an association of treatment duration and lack of XLH-family history with higher BMI-IOTF.
CONCLUSION: 1/3 of XLH-children have phenotypically unfavourable metabolic profile expressed as increased prevalence of overweight/obesity. Both the lack of XLH family history and duration of treatment increase the risk of higher BMI-IOTF. BMI should be carefully monitored in children and later adults, with XLH.

PMID: 31910157 [PubMed - as supplied by publisher]

A New Way to Discover IRESs in Pathology or Stress Conditions? Harnessing Latest High-Throughput Technologies.

Bioessays. 2020 Jan 07;:e1900180

Authors: Wang LY, Cui JJ, Guo CX, Yin JY

Abstract
The cellular internal ribosomal entry site (IRES) is one of the most important elements to mediate cap-independent translational initiation, especially under conditions of stress and pathology. However, a high-throughput method to discover IRESs in these conditions is still lacking. Here, a possible way IRES long-read sequencing based on the latest high-throughput technologies is proposed to solve this problem. Based on this design, diversity and integrity of the transcriptome from original samples can be kept. The micro-environment that stimulates or inhibits IRES activity can also be mimicked. By using long read-length sequencing technology, additional experiments that are essential for ruling out the cryptic promoters or splicing events in routine IRES identification processes can be circumvented. It is hoped that this proposed methodology may be adopted for IRES element discovery, hence uncovering the full extent of the role of IRESs in disease, development, and stress.

PMID: 31909834 [PubMed - as supplied by publisher]

KRCC1: A potential therapeutic target in ovarian cancer.

FASEB J. 2019 Dec 23;:

Authors: Dwivedi SKD, Shameer K, Dey A, Mustafi SB, Xiong X, Bhattacharya U, Neizer-Ashun F, Rao G, Wang Y, Ivan C, Yang D, Dudley JT, Xu C, Wren JD, Mukherjee P, Bhattacharya R

Abstract
Using a systems biology approach to prioritize potential points of intervention in ovarian cancer, we identified the lysine rich coiled-coil 1 (KRCC1), as a potential target. High-grade serous ovarian cancer patient tumors and cells express significantly higher levels of KRCC1 which correlates with poor overall survival and chemoresistance. We demonstrate that KRCC1 is predominantly present in the chromatin-bound nuclear fraction, interacts with HDAC1, HDAC2, and with the serine-threonine phosphatase PP1CC. Silencing KRCC1 inhibits cellular plasticity, invasive properties, and potentiates apoptosis resulting in reduced tumor growth. These phenotypes are associated with increased acetylation of histones and with increased phosphorylation of H2AX and CHK1, suggesting the modulation of transcription and DNA damage that may be mediated by the action of HDAC and PP1CC, respectively. Hence, we address an urgent need to develop new targets in cancer.

PMID: 31908025 [PubMed - as supplied by publisher]

[Too early for pharmacogenetics in psychiatric practice? Implementation is in full swing].

Tijdschr Psychiatr. 2019;61(10):678-680

Authors: van Westrhenen R, Bet PM, van Weelden M, van Schaik RHN

PMID: 31907910 [PubMed - in process]

"Bridging the Gap" Everything that Could Have Been Avoided If We Had Applied Gender Medicine, Pharmacogenetics and Personalized Medicine in the Gender-Omics and Sex-Omics Era.

Int J Mol Sci. 2019 Dec 31;21(1):

Authors: Gemmati D, Varani K, Bramanti B, Piva R, Bonaccorsi G, Trentini A, Manfrinato MC, Tisato V, Carè A, Bellini T

Abstract
. Gender medicine is the first step of personalized medicine and patient-centred care, an essential development to achieve the standard goal of a holistic approach to patients and diseases. By addressing the interrelation and integration of biological markers (i.e., sex) with indicators of psychological/cultural behaviour (i.e., gender), gender medicine represents the crucial assumption for achieving the personalized health-care required in the third millennium. However, 'sex' and 'gender' are often misused as synonyms, leading to frequent misunderstandings in those who are not deeply involved in the field. Overall, we have to face the evidence that biological, genetic, epigenetic, psycho-social, cultural, and environmental factors mutually interact in defining sex/gender differences, and at the same time in establishing potential unwanted sex/gender disparities. Prioritizing the role of sex/gender in physiological and pathological processes is crucial in terms of efficient prevention, clinical signs' identification, prognosis definition, and therapy optimization. In this regard, the omics-approach has become a powerful tool to identify sex/gender-specific disease markers, with potential benefits also in terms of socio-psychological wellbeing for each individual, and cost-effectiveness for National Healthcare systems. "Being a male or being a female" is indeed important from a health point of view and it is no longer possible to avoid "sex and gender lens" when approaching patients. Accordingly, personalized healthcare must be based on evidence from targeted research studies aimed at understanding how sex and gender influence health across the entire life span. The rapid development of genetic tools in the molecular medicine approaches and their impact in healthcare is an example of highly specialized applications that have moved from specialists to primary care providers (e.g., pharmacogenetic and pharmacogenomic applications in routine medical practice). Gender medicine needs to follow the same path and become an established medical approach. To face the genetic, molecular and pharmacological bases of the existing sex/gender gap by means of omics approaches will pave the way to the discovery and identification of novel drug-targets/therapeutic protocols, personalized laboratory tests and diagnostic procedures (sex/gender-omics). In this scenario, the aim of the present review is not to simply resume the state-of-the-art in the field, rather an opportunity to gain insights into gender medicine, spanning from molecular up to social and psychological stances. The description and critical discussion of some key selected multidisciplinary topics considered as paradigmatic of sex/gender differences and sex/gender inequalities will allow to draft and design strategies useful to fill the existing gap and move forward.

PMID: 31906252 [PubMed - in process]

Relationship between genetic variation in the α2A-adrenergic receptor and the cardiovascular effects of dexmedetomidine in the Chinese Han population.

J Zhejiang Univ Sci B. 2019 Jul;20(7):598-604

Authors: Zhu SJ, Wang KR, Zhang XX, Zhu SM

Abstract
There are differences in individual cardiovascular responses to the administration of dexmedetomidine, a highly selective α2A-adrenergic receptor (ADRA2A) agonist. The aim of this study was to investigate ADRA2A gene polymorphisms in the Chinese Han population and their association with the cardiovascular response to intravenous dexmedetomidine infusion. Sixty elective surgery patients of Chinese Han nationality were administered 1 µg/kg dexmedetomidine intravenously over 10 min as a premedication. ADRA2A C-1291G and A1780G polymorphism status was determined in these patients, and their relationships to changes in blood pressure and heart rate after dexmedetomidine administration were analyzed. There were neither significant differences in systolic or diastolic blood pressure changes in individuals with different A1780G and C-1291G genotypes after dexmedetomidine administration, nor in heart rates among the different A1780G genotypes. However, there were significant differences in changes in heart rates in patients with different C-1291G genotypes. There were no significant differences in the sedative effects of dexmedetomidine among different A1780G and C-1291G genotypes. Logistic regression revealed that the C-1291G polymorphism was associated with differential decreases in heart rate after intravenous infusion of dexmedetomidine. These findings indicate that the ADRA2A C-1291G polymorphism can affect heart rate changes in patients after intravenous infusion of dexmedetomidine.

PMID: 31168973 [PubMed - indexed for MEDLINE]

16 new pubmed citations were retrieved for your search. Click on the search hyperlink below to display the complete search results:

pharmacogenomics

These pubmed results were generated on 2020/01/07

PubMed comprises more than millions of citations for biomedical literature from MEDLINE, life science journals, and online books. Citations may include links to full-text content from PubMed Central and publisher web sites.

Pharmacology of tyrosine kinase inhibitors in chronic myeloid leukemia; a clinician's perspective.

Daru. 2020 Jan 03;:

Authors: Pushpam D, Bakhshi S

Abstract
OBJECTIVE: In this review, we have summarized the pharmacokinetics, pharmacodynamics and adverse effects of imatinib, dasatinib, nilotinib, bosutinib, ponatinib and radotinib with focus on pharmacogenomic studies with clinical end points. We have discussed the key phase 3 trials of tyrosine kinase inhibitors (TKI) comparing with each other, treatment free remission (TFR) and selection of TKI. Upcoming concepts and related trials in the management of chronic myeloid leukemia (CML) along with future directions have been touched upon.
EVIDENCE ACQUISITION: PubMed, Embase, Google, Cochrane library and Medline were searched to identify relevant literature for the review. Clinicaltrial.gov was searched for upcoming data and trials.
RESULTS: There are lot of gap in pharmacokinetics and pharmacodynamics of TKI. Imatinib appears to be the safest TKI. Newer TKI's achieve better achievement of therapeutic milestones, deeper molecular response and less chances of progression of CML compared to imatinib. Newer TKI appears to be better choice for achieving TFR. When the objective is survival, imatinib is still the TKI of choice. Primary prophylaxis with antiplatelet drugs for TKI having cardiovascular and thromboembolic side effects should be considered.
CONCLUSION: Pharmacogenetic data of TKI is still immature to guide in therapeutic decision making in clinical practice. There is need for further research in pharmacology and pharmacogenomics of newer TKI's. Randomized controlled trials are required to decide the optimum TKI for TFR. Safe and effective TKI for targeting T315I mutation, CML accelerated phase and blast crisis are an active area of research.

PMID: 31900888 [PubMed - as supplied by publisher]

Status Epilepticus: The Slow and Agonizing Death of Phenytoin.

J Pediatr Pharmacol Ther. 2020 Jan-Feb;25(1):4-6

Authors: Hall EA, Wheless JW, Phelps SJ

Abstract
Since its introduction in 1950, phenytoin (PHT) has been the premier parenteral anticonvulsant used in the management of generalized convulsive status epileptics (GCSE) that is refractory to benzodiazepines. Without question, its arrival was vital to the care of patients with acute seizures and was a welcomed alternative to paraldehyde and phenobarbital. However, after more than half a century of use, there continues to be insufficient evidence-based data to support its efficacy over other anticonvulsants as a first-line agent in pediatric or adult patients with GCSE. This coupled with its narrow mechanism of action, complex pharmacokinetics and pharmacogenomics, drug-drug interactions, unique adverse effects, and formulation issues that make administration difficult mandates that PHT be replaced by safer and superiorly effective anticonvulsants for the treatment of GCSE when benzodiazepines are ineffective. We believe that levetiracetam should become the preferred agent for seizures unresponsive to or recurring after treatment with a benzodiazepine as it is at least equally effective to PHT and has several important advantages. PHT has overstayed its welcome and it is simply time for it to exit the realm of acute seizure management as a first-line agent for benzodiazepine-refractory GCSE.

PMID: 31897070 [PubMed]

NF-kB signaling in cardiomyocytes is inhibited by sevoflurane and promoted by propofol.

FEBS Open Bio. 2020 Jan 03;:

Authors: Oda-Kawashima K, Sedukhina AS, Okamoto N, Lytvyn M, Minagawa K, Iwata T, Kumai T, Sato E, Inada E, Yamaura A, Sakamoto M, Roche-Molina M, Bernal JA, Sato K

Abstract
Both inhalational and intravenous anesthetics affect myocardial remodeling, but the precise effect of each anesthetic on molecular signaling in myocardial remodeling is unknown. Here, we performed in silico analysis to investigate signaling alterations in cardiomyocytes induced by inhalational (sevoflurane) and intravenous (propofol) anesthetics. Bioinformatics analysis revealed that NF-kB signaling was inhibited by sevoflurane and promoted by propofol. Moreover, nuclear accumulation of p65 and transcription of NF-kB-regulated genes were suppressed in sevoflurane-administered mice, suggesting that sevoflurane inhibits the NF-kB signaling pathway. Our data demonstrate that NF-kB signaling is inhibited by sevoflurane and promoted by propofol. As NF-kB signaling plays an important role in myocardial remodeling, our results suggest that anesthetics may affect myocardial remodeling through NF-kB.

PMID: 31898867 [PubMed - as supplied by publisher]

Valproic Acid Decreases Endothelial Colony Forming Cells Differentiation and Induces Endothelial-to-Mesenchymal Transition-like Process.

Stem Cell Rev Rep. 2020 Jan 02;:

Authors: Nevo N, Lecourt S, Bièche I, Kucia M, Cras A, Blandinieres A, Vacher S, Gendron N, Guerin CL, Ratajczak MZ, Smadja DM

Abstract
Valproic acid (VPA), a histone deacetylase (HDAC) inhibitor is a widely used anticonvulsant drug. VPA is also under clinical evaluation to be employed in anticancer therapy, as an antithrombotic agent or a molecule to be used in the stem cells expansion protocols. Since endothelial colony forming cells (ECFC) has been identified as the human postnatal vasculogenic cells involved in thrombotic disorders and serve as a promising source of immature cell for vascular repair, objectives of the present study were to determine how VPA contributes to ECFC commitment and their angiogenic properties. We examined the effect of VPA on ECFC obtained from cord blood by evaluating colony number, proliferation, migration and their sprouting ability in vitro, as well as their in vivo vasculogenic properties. VPA inhibited endothelial differentiation potential from of cord blood derived stem cells associated with decreased proliferation and sprouting activity of cultured ECFC. VPA treatment significantly decreased the vessel-forming ability of ECFC transplanted together with mesenchymal stem cells (MSC) in Matrigel implants in nude mice model. Surprisingly, a microscopic evaluation revealed that VPA induces marked morphological changes from a cobblestone-like EC morphology to enlarged spindle shaped morphology of ECFC. RT-qPCR and a CD31/CD90 flow cytometry analysis confirmed a phenotypic switch of VPA-treated ECFC to mesenchymal-like phenotype. In conclusion, the pan-HDAC inhibitor VPA described for expansion of hematopoietic stem cells and very small embryonic like stem cells cannot be successfully employed for differentiation of endothelial lineage committed ECFC into functional endothelial cells. Our data also suggest that VPA based therapeutics may induce endothelial dysfunction associated with fibrosis that might induce thrombosis recurrence or venous insufficiency.

PMID: 31898801 [PubMed - as supplied by publisher]

Biochemical parameters in determination of nutritional status in amyotrophic lateral sclerosis.

Neurol Sci. 2020 Jan 02;:

Authors: Chełstowska B, Kuźma-Kozakiewicz M

Abstract
OBJECTIVES: Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder without effective treatment. Progressive dysphagia, depression, and hypermetabolism may lead to malnutrition. The aim of the present study was to analyze the potential utility of readily available, relatively inexpensive, and rapid strategy for using laboratory parameters to assess nutritional status of ALS patients.
METHODS: This study included 203 patients with ALS. The analysis of inflammatory parameters: C Reactive Protein (CRP), erythrocyte sedimentation rate (ESR), white blood cell count (WBC), lymphocytes number (LN), and fibrinogen concentration (FC) was followed by nutritional markers: serum concentration of albumin (ALB), prealbumin (PALB), transferrin (TRNF), and creatinine (CREA), which were correlated with demographic and clinical parameters: body mass index (BMI), ALS phenotype, disease duration, diagnosis delay, and functional and respiratory assessment.
RESULTS: Nearly 20% of patients had biochemical features of inflammation. Among patients without inflammation (n = 163), a decreased serum TRNF concentration was found in 84% of cases, PALB in 39%, ALB in 25%, and CREA in 53%. The median of PALB was the highest in patients with PMA (23.5 mg/dL) and the lowest in PBP (16.6 mg/dL) (p < 0.05). The CREA concentration correlated with the BMI (r = 0.25; p < 0.01), while PALB and TRNF significantly varied depending on the severity of dysphagia. Patients with dysphagia qualified to enteral nutrition showed significantly decreased concentration of PALB, triglycerides, as well as reduced forced vital capacity, BMI, and functional status.
CONCLUSIONS: CREA, PALB, ALB, and TNFR are easily accessible, accurate, and low-cost parameters useful in assessment of the nutritional status in ALS.

PMID: 31897946 [PubMed - as supplied by publisher]

Genome Editing Session: Trends and Core Functions for CRISPR-Directed Gene Editing.

J Biomol Tech. 2019 Dec;30(Suppl):S51-S52

Authors: Kmiec EB

Abstract
While this CRISPR-directed gene editing is revolutionizing genetics, gene therapy and even cancer diagnostics, its application is not without challenges. We'll open the session with an overview of a gene editing core that carries out pharmacogenomics as a service business and provides educational opportunities. We will then address several scientific challenges in both execution and analyses that can impede workers in the field, providing information as to how core directors are working to address these problems. These challenges include 1) Specificity: fidelity of gene editing is a centerpiece of this technology yet target range remains a challenge. To improve the targeting range and enzymatic activity of Cas12a, Michael Collingwood will describe a bacterial-based selection assay to select for Cas12a mutants that demonstrate increased cleavage activity and reduced PAM specificity. Overall, this new variant with enhanced activity and broadened PAM compatibility could allow for broader application of the CRISPR-Cas12a system for genome editing; 2) Analyses of Genomic Changes: quantifying editing rates in pools of cells or identifying correctly edited clones can be complex and is always tedious.Although targeted NGS provides a high-throughput platform for optimizing editing reagents and identifying correctly modified clones, thelarge amount of data produced can be difficult to analyze. Shondra Miller will talk about a new system, CRIS.py, a simple and highly versatile python-based program, which can concurrently analyze next-generation sequencing data for both knock-out and multiple user-specified knock-in modifications from one or many edited samples; 3) Gene Editing in a Mouse Model; The mouse remains a preferred organism for creating genetically modified animal models especially for testing novel and innovative gene editing strategies. C. (Guru) Gurumurthy will cover the paradigm shifts caused by the CRISPR tool, as well as the latest CRISPR trends in mouse genome engineering. This comprehensive overview will be interspersed with a dynamic dialogue with the audience.

PMID: 31896996 [PubMed - in process]

PGxCorpus, a manually annotated corpus for pharmacogenomics.

Sci Data. 2020 Jan 02;7(1):3

Authors: Legrand J, Gogdemir R, Bousquet C, Dalleau K, Devignes MD, Digan W, Lee CJ, Ndiaye NC, Petitpain N, Ringot P, Smaïl-Tabbone M, Toussaint Y, Coulet A

Abstract
Pharmacogenomics (PGx) studies how individual gene variations impact drug response phenotypes, which makes PGx-related knowledge a key component towards precision medicine. A significant part of the state-of-the-art knowledge in PGx is accumulated in scientific publications, where it is hardly reusable by humans or software. Natural language processing techniques have been developed to guide experts who curate this amount of knowledge. But existing works are limited by the absence of a high quality annotated corpus focusing on PGx domain. In particular, this absence restricts the use of supervised machine learning. This article introduces PGxCorpus, a manually annotated corpus, designed to fill this gap and to enable the automatic extraction of PGx relationships from text. It comprises 945 sentences from 911 PubMed abstracts, annotated with PGx entities of interest (mainly gene variations, genes, drugs and phenotypes), and relationships between those. In this article, we present the corpus itself, its construction and a baseline experiment that illustrates how it may be leveraged to synthesize and summarize PGx knowledge.

PMID: 31896797 [PubMed - in process]

Association of carbamazepine-induced Stevens-Johnson syndrome/toxic epidermal necrolysis with the HLA-B75 serotype or HLA-B*15:21 allele in Filipino patients.

Pharmacogenomics J. 2020 Jan 03;:

Authors: Capule F, Tragulpiankit P, Mahasirimongkol S, Jittikoon J, Wichukchinda N, Theresa Alentajan-Aleta L, James Barit JV, Casanova-Gutierrez J, Cabral-Lim L, Baltazar Reyes JP, Roa F, Salonga R, San Gabriel KF, Lynn Silao C

Abstract
A case-control study was conducted to investigate the association of HLA-A alleles, HLA-B alleles including HLA-B*15:02 and HLA-B75 serotype with carbamazepine-induced SJS/TEN in Filipino patients. A retrospective review of medical records was performed. Pertinent clinical data were collected. Eight (8) carbamazepine-induced SJS/TEN cases and 32 tolerant controls were recruited. Genomic DNA was extracted from the saliva samples and genotyping was performed by employing allele-specific polymerase chain reaction. Data were analyzed using the Fisher's exact test, Mann-Whitney U test, univariate logistic regression, and multivariate logistic regression. Single allele association analysis was done. The strength of association was expressed as odds ratio with 95% confidence interval. Positive predictive value, negative predictive value, sensitivity, and specificity were computed. Of all the alleles tested, the HLA-B75 serotype (p = 0.007, OR = 23.25, 95% CI = 2.33-232.21) and HLA-B*15:21 (p = 0.026, OR = 7.53, 95% CI = 1.27-44.79) were significantly associated with carbamazepine-induced SJS/TEN. The HLA-B75 serotype or HLA-B*15:21 allele may be used as a genetic risk assessment prior to prescription for prevention of carbamazepine-induced SJS/TEN in Filipino patients.

PMID: 31896765 [PubMed - as supplied by publisher]

ABCB1 and DRD3 polymorphism as a response predicting biomarker and tool for pharmacogenetically guided clozapine dosing in Asian Indian treatment resistant schizophrenia patients.

Asian J Psychiatr. 2019 Dec 26;48:101918

Authors: M N, Patil AN, Pattanaik S, Kaur A, Banerjee D, Grover S

Abstract
PURPOSE: To investigate association of two single nucleotide polymorphisms (SNPs) ABCB1(rs1045462) and DRD3(rs6280) with clozapine response and the dose in treatment resistant schizophrenia (TRS) patients.
METHODS: 200 TRS patients were enrolled in the study during their follow up visit post clozapine initiation. SNP assessment was performed for DRD3 (rs6280) and ABCB1(rs1045462) by sequencing. Blood sample for genotyping was collected with disease and treatment related variables recording on case record form. Patients were classified as responders or nonresponders based upon Andreasen criteria and Positive and Negative Syndrome Scale (PANSS).
RESULTS: Mean clozapine dose, the genotype frequency distribution of ABCB1, DRD3 SNPs were significantly different in clozapine responder and non-responder study population (p < 0.05). CT genotype of ABCB1 and AG genotype of DRD3 were observed to be more prevalent in the responder group. TT genotype of ABCB1 and AG genotype of DRD3 were prevalent in the nonresponder group. Clozapine dosing equations for responder and nonresponder TRS populations were developed through logistic regression analysis. 27% variability in clozapine dose was explained by possible combinations of ABCB1 and DRD3 SNP analysis.
CONCLUSION: Differential ABCB1(rs1045462) and DRD3(rs6280) genotype frequencies among the clozapine responders and non-responders explained clear feasibility of response predictor potential along with clozapine dose variability association. Pharmacogenetically guided clozapine dosing is possible if more SNPs are considered together with ABCB1(rs1045462) and DRD3(rs6280) in TRS patients.

PMID: 31896438 [PubMed - as supplied by publisher]

Implementation and Outcomes of a Molecular Tumor Board at Herbert-Herman Cancer Center, Sparrow Hospital.

Acta Med Acad. 2019 Apr;48(1):105-115

Authors: Trivedi H, Acharya D, Chamarthy U, Meunier J, Ali-Ahmad H, Hamdan M, Herman J, Srkalovic G

Abstract
OBJECTIVE: This paper describes our experience and outcomes from 54 cases presented to the (Molecular tumor board) MTB.
METHODS: 54 Cases presented between July 2017 and April 2018 were included in this analysis. These patients had different types of cancers that had either failed standard therapy or were expected to fail and physicians were looking for future options for anticipated progression. Patients who had obvious mutations and were candidates for Targeted Agent and Profiling Utilization Registry or Molecular Analysis for Treatment Choice clinical trials were not included. Oncologists presented the cases virtually and Foundation Medicine scientific and clinical team discussed the molecular pathways to find targeted options or trials. Tumor board attendees included oncologists, nurses, pharmacists, mid-level providers, residents and staff of the Cancer Center.
RESULTS: Amongst the 54 cases presented 81% had one or more potentially actionable alteration. 12 (22%) patients received genomically matched therapy as per MTB recommendations. Additional 13 (24%) patients have options available when they progress. Out of 12 patients who got treatment six are alive at the time of this analysis. Genomically matched therapy or Clinical Trials option were offered to the 46% of patients based on the MTB discussion.
CONCLUSION: More widespread use of molecular diagnostics, better physician education and multidisciplinary collaboration between the staff involved in diagnosis and treatment, as well as third party payers are necessary for consensus on treatment and care of oncology patients.

PMID: 31264438 [PubMed - indexed for MEDLINE]

Beta-blocker Dose Stratifies Mortality Risk in a Racially Diverse Heart Failure Population.

J Cardiovasc Pharmacol. 2019 Dec 31;:

Authors: Lteif C, Arwood MJ, Kansal M, Cavallari LH, Desai AA, Duarte JD

Abstract
Heart failure (HF) is highly prevalent and a major cause of death in the US. The effect of HF medications on survival has been predicted by validated models studied in populations predominantly of European descent. This study aimed to identify medications associated with survival in a racially diverse HF population. HF patients were recruited and followed from 2001 to 2015. Data were collected from electronic health records and the Social Security Death Index. The primary analysis tested the association between medication dose and all-cause mortality, with a secondary analysis assessing the composite outcome of death or cardiac-related hospitalization. Circulating concentration of the fibrotic marker procollagen type III N-terminal peptide (PIIINP) was also compared with medication doses in patients with concentrations available. The study population consisted of 337 patients, of which 23% died and 46% were hospitalized. Increased beta blocker (BB) dose was significantly associated with survival in the base model (HR=0.71, P=0.017), and marginally associated in the comprehensive model (HR=0.75, P= 0.068). BB dose was also associated with decreased risk of the composite endpoint in the base model (HR= 0.80, P=0.029) and to a lesser extent in the comprehensive model (HR=0.83, P=0.085). Further, increased BB dose was inversely associated with circulating PIIINP concentration (P=0.041). In conclusion, our study highlights the importance of BB dose escalation for survival and decreased hospitalization in patients with HF, regardless of race or HF type. It also suggests that benefits observed with high-dose BBs could be mediated, at least in part, by decreased cardiac fibrosis, however further research is needed.

PMID: 31895871 [PubMed - as supplied by publisher]