219 results match your criteria Fluorouracil Toxicity and DPYD


Impact of DPYD, DPYS and UPB1 gene variations on severe drug-related toxicity in cancer patients.

Cancer Sci 2020 Jul 3. Epub 2020 Jul 3.

Division of Molecular Genetics, Institute for Comprehensive Medical Science, Fujita Health University, Toyoake, Japan.

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS and UPB1 genes. Genotype-guided dose individualization of FP therapy has been proposed in Western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP-related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intronic regions of their DPYD, DPYS and UPB1 genes. Read More

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http://dx.doi.org/10.1111/cas.14553DOI Listing

Evaluation of adverse effects of chemotherapy regimens of 5-fluoropyrimidines derivatives and their association with DPYD polymorphisms in colorectal cancer patients.

BMC Cancer 2020 Jun 16;20(1):560. Epub 2020 Jun 16.

Department of Pathology, Imam Khomeini Hospital, Mazandaran University of Medical Sciences, Sari, Iran.

Background: 5-Fluorouracil (5-FU) and capecitabine are fluoropyrimidine derivatives that mainly metabolized with dihydropyrimidine dehydrogenase enzyme (DPD). The genetic polymorphism in the genes encoding this enzyme may result in a decrease or loss of enzyme activity which may lead to the accumulation of medicines, their metabolites and potential toxicity.

Method: This cross-sectional study was conducted on 88 participants with colorectal cancer (CRC). Read More

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http://dx.doi.org/10.1186/s12885-020-06904-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298798PMC

Clinical evaluation of germline polymorphisms associated with capecitabine toxicity in breast cancer: TBCRC-015.

Breast Cancer Res Treat 2020 Jun 6;181(3):623-633. Epub 2020 May 6.

The University of Chicago, 5841 S. Maryland Avenue, MC 2115, Chicago, IL, 60637, USA.

Purpose: Capecitabine is important in breast cancer treatment but causes diarrhea and hand-foot syndrome (HFS), affecting adherence and quality of life. We sought to identify pharmacogenomic predictors of capecitabine toxicity using a novel monitoring tool.

Methods: Patients with metastatic breast cancer were prospectively treated with capecitabine (2000 mg/m/day, 14 days on/7 off). Read More

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http://dx.doi.org/10.1007/s10549-020-05603-8DOI Listing

DPD Testing Before Treatment With Fluoropyrimidines in the Amsterdam UMCs: An Evaluation of Current Pharmacogenetic Practice.

Front Pharmacol 2019 28;10:1609. Epub 2020 Jan 28.

Department of Clinical Genetics, Section Community Genetics, Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Introduction: The fluoropyrimidines (FP) (5-Fluorouracil, capecitabine, and tegafur) are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10-40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend genotyping before treatment with FP. Read More

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http://dx.doi.org/10.3389/fphar.2019.01609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997151PMC
January 2020

Fluorouracil sensitivity in a head and neck squamous cell carcinoma with a somatic structural variant.

Cold Spring Harb Mol Case Stud 2020 Feb 3;6(1). Epub 2020 Feb 3.

Department of Medical Oncology, BC Cancer, Vancouver, British Columbia V5Z 4E6, Canada.

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and represents a heterogeneous group of tumors, the majority of which are treated with a combination of surgery, radiation, and chemotherapy. Fluoropyrimidine (5-FU) and its oral prodrug, capecitabine, are commonly prescribed treatments for several solid tumor types including HNSCC. 5-FU-associated toxicity is observed in ∼30% of treated patients and is largely caused by germline polymorphisms in , which encodes dihydropyrimidine dehydrogenase, a key enzyme of 5-FU catabolism and deactivation. Read More

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http://dx.doi.org/10.1101/mcs.a004713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6996515PMC
February 2020

Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines.

Eur J Hum Genet 2020 Apr 19;28(4):508-517. Epub 2019 Nov 19.

Department of Clinical Pharmacy & Toxicology, Leiden University Medical Centre, Leiden, The Netherlands.

Despite advances in the field of pharmacogenetics (PGx), clinical acceptance has remained limited. The Dutch Pharmacogenetics Working Group (DPWG) aims to facilitate PGx implementation by developing evidence-based pharmacogenetics guidelines to optimize pharmacotherapy. This guideline describes the starting dose optimization of three anti-cancer drugs (fluoropyrimidines: 5-fluorouracil, capecitabine and tegafur) to decrease the risk of severe, potentially fatal, toxicity (such as diarrhoea, hand-foot syndrome, mucositis or myelosuppression). Read More

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http://dx.doi.org/10.1038/s41431-019-0540-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7080718PMC

A case-control study to assess the ability of the thymine challenge test to predict patients with severe to life threatening fluoropyrimidine-induced gastrointestinal toxicity.

Br J Clin Pharmacol 2020 01 12;86(1):155-164. Epub 2019 Dec 12.

Blood and Cancer, Auckland City Hospital, Grafton, Auckland, New Zealand.

Aims: A previous study suggested that a thymine (THY) challenge dose could detect aberrant pharmacokinetics in known cases of fluoropyrimidine toxicity compared with healthy volunteers. The preliminary data suggested that urine sampling also could detect this aberrant disposition. The aim of this case-control study was to assess the ability of the urinary THY challenge test to discriminate cases of severe gastrointestinal toxicity in a cohort of patients treated with 5-fluorouracil or capecitabine. Read More

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http://dx.doi.org/10.1111/bcp.14153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6983507PMC
January 2020

Prevalence of the DPYD variant (Y186C) in Brazilian individuals of African ancestry.

Cancer Chemother Pharmacol 2019 Dec 22;84(6):1359-1363. Epub 2019 Oct 22.

Department of Internal Medicine, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.

Purpose: The presence of deleterious variants of dihydropyrimidine-dehydrogenase gene (DPYD) is associated with 5-Fluorouracil toxicity. Most of the data are based on findings in Caucasian populations. The variant Y186C (rs115232898) is found almost exclusively in African populations and is related to low DPD function. Read More

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http://dx.doi.org/10.1007/s00280-019-03974-4DOI Listing
December 2019
1 Read

Identifying a Novel DPYD Polymorphism Associated with Severe Toxicity to 5-FU Chemotherapy in a Saudi Patient.

Case Rep Genet 2019 21;2019:5150725. Epub 2019 Aug 21.

Department of Internal Medicine, King Abdulaziz University, Jeddah, Saudi Arabia.

Dihydropyrimidine dehydrogenase (DPD) is the major enzyme in the catabolism of 5-Fluorouracil (5-FU) and its prodrug capecitabine. We report a 65-year-old female with rectal adenocarcinoma who experienced severe toxicities secondary to standard dose 5-FU based chemotherapy. She was found to be heterozygous for rs371313778, c. Read More

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https://www.hindawi.com/journals/crig/2019/5150725/
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http://dx.doi.org/10.1155/2019/5150725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720358PMC
August 2019
4 Reads

Lethal toxicities after capecitabine intake in a previously 5-FU-treated patient: why dose matters with dihydropryimidine dehydrogenase deficiency.

Pharmacogenomics 2019 08;20(13):931-938

Medical Biology Department, APHM Marseille, France.

Dihydropryimidine dehydrogenase (DPD) deficiency is a pharmacogenetic syndrome associated with severe or lethal toxicities with oral capecitabine. Usually, patients with history of 5-FU-based therapy with no signs for life-threatening toxicities are considered as not DPD-deficient individuals who can be safely treated next with capecitabine if required. Here we describe the case of a woman originally treated with standard FEC100 protocol for metastatic breast cancer with little severe toxicities but grade-3 mucosities that were quickly resolved by symptomatic treatment. Read More

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https://www.futuremedicine.com/doi/10.2217/pgs-2019-0028
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http://dx.doi.org/10.2217/pgs-2019-0028DOI Listing
August 2019
3 Reads
3.218 Impact Factor

ToxNav germline genetic testing and PROMinet digital mobile application toxicity monitoring: Results of a prospective single-center clinical utility study-PRECISE study.

Cancer Med 2019 10 4;8(14):6305-6314. Epub 2019 Sep 4.

Oxford Cancer Biomarkers, Oxford Science Park, Oxford, UK.

Introduction: In this study (PRECISE), we assess the clinical utility of a germline DNA sequencing-based test (ToxNav) for mutations in DPYD and ENOSF1 genes to alter clinician-prescribed fluoropyrimidine doses and the use of a digital application (PROMinet) to record patient-reported chemotherapy toxicity.

Materials And Methods: Adult patients with a histological diagnosis of colorectal cancer (CRC) who consented to fluoropyrimidine-based chemotherapy were recruited prospectively and given a digital application to monitor and record associated toxicities. Patient samples were analyzed for 18 germline coding variants in DPYD and 1 ENOSF1 variant. Read More

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http://dx.doi.org/10.1002/cam4.2529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797583PMC
October 2019
4 Reads

The Prevalence of DPYD*9A(c.85T>C) Genotype and the Genotype-Phenotype Correlation in Patients with Gastrointestinal Malignancies Treated With Fluoropyrimidines: Updated Analysis.

Clin Colorectal Cancer 2019 09 3;18(3):e280-e286. Epub 2019 May 3.

Medical Oncology, The University of South Alabama, Mitchell Cancer Institute, Mobile, AL. Electronic address:

Introduction: The dihydropyrimidine dehydrogenase gene (DPYD)*9A (c.85T>C) genotype is relatively common. The correlation between DPYD*9A genotype and dihydropyrimidine dehydrogenase (DPD) deficiency phenotype is controversial. Read More

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http://dx.doi.org/10.1016/j.clcc.2019.04.005DOI Listing
September 2019
9 Reads
2.907 Impact Factor

Severe adverse events due to dihydropyrimidine dehydrogenase deficiency in a Japanese patient with colon cancer taking capecitabine: a case report.

Int Cancer Conf J 2018 Oct 15;7(4):125-129. Epub 2018 Jun 15.

Department of Surgery, Hiratsuka City Hospital, 1-19-1, Minamihara, Hiratsuka, Kanagawa 254-0065 Japan.

Fluoropyrimidine has been commonly used not only in unresectable cases of metastatic colorectal cancer, but also in adjuvant therapy. Dihydropyrimidine dehydrogenase (DPD) is an enzyme encoded by the , which is responsible for the rate-limiting step in pyrimidine catabolism and breaks down more than 80% of standard doses of 5-fluorouracil (5-FU) and capecitabine, an oral prodrug of 5-FU. The lack of enzymatic activity increases the half-life of the drug, resulting in excess drug accumulation and toxicity which may lead to life-threatening side effects. Read More

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http://dx.doi.org/10.1007/s13691-018-0334-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6498256PMC
October 2018
22 Reads

A case report of a severe fluoropyrimidine-related toxicity due to an uncommon DPYD variant.

Medicine (Baltimore) 2019 May;98(21):e15759

Oncologia Medica, Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli, Napoli.

Introduction: Fluoropyrimidines such as 5-fluorouracil (5-FU) and its orally active prodrug, capecitabine, are widely used in the treatment of gastrointestinal cancer, including colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) plays an important role in the 5-FU metabolism. Dihydropyrimidine dehydrogenase gene (DPYD) is a highly polymorphic gene with several hundreds of reported genetic variants and DPD activity levels vary considerably among individuals, with different 5-FU-related efficacy and toxicity. Read More

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http://dx.doi.org/10.1097/MD.0000000000015759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571425PMC
May 2019
15 Reads

Three different polymorphisms of the DPYD gene associated with severe toxicity following administration of 5-FU: a case report.

J Med Case Rep 2019 Mar 22;13(1):76. Epub 2019 Mar 22.

Department of Surgery, HPB and Liver Transplant Unit, American University of Beirut, PO Box 11-0236, Riad El Solh, Beirut, 1107 2020, Lebanon.

Background: Dihydropyrimidine dehydrogenase deficiency secondary to polymorphisms in the DPYD gene can lead to significant toxicity associated with the administration of fluoropyrimidine chemotherapy.

Case Presentation: We report a case of a 59-year-old Lebanese woman with metastatic pancreatic cancer who received FOLFIRINOX therapy and developed severe 5-fluorouracil toxicity after a single cycle. The entire DPYD gene was sequenced, and the patient was found to be heterozygous for three different polymorphisms that have reportedly been associated with dihydropyrimidine dehydrogenase deficiency. Read More

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http://dx.doi.org/10.1186/s13256-019-2013-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429833PMC
March 2019
8 Reads

The clinical relevance of multiple DPYD polymorphisms on patients candidate for fluoropyrimidine based-chemotherapy. An Italian case-control study.

Br J Cancer 2019 04 12;120(8):834-839. Epub 2019 Mar 12.

Medical Oncology Unit, Clinical Cancer Centre, Azienda USL-IRCCS di Reggio Emilia, Reggio Emilia, Italy.

Background: Deleterious polymorphisms in the gene encoding DPD (DPYD) may result in severe reduction of DPD enzymatic activity that causes life-threatening toxicities when the standard dose of fluorouracil is used. The best panel of single-nucleotide polymorphism (SNPs) of DPYD is not well defined.

Methods: In 2011, we began screening DPYD*2A in patients candidate for fluoropyrimidine-based chemotherapy. Read More

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http://dx.doi.org/10.1038/s41416-019-0423-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6474277PMC
April 2019
46 Reads

Clinical implementation of pre-treatment DPYD genotyping in capecitabine-treated metastatic breast cancer patients.

Breast Cancer Res Treat 2019 Jun 12;175(2):511-517. Epub 2019 Feb 12.

Breast Unit, Guy's and St Thomas' NHS Foundation Trust and King's Biomedical Centre, 4th Floor, Bermondsey Wing, Great Maze Pond, London, SE1 9RT, UK.

Purpose: Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. Read More

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http://dx.doi.org/10.1007/s10549-019-05144-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533219PMC
June 2019
10 Reads

A cost analysis of upfront DPYD genotype-guided dose individualisation in fluoropyrimidine-based anticancer therapy.

Eur J Cancer 2019 01 11;107:60-67. Epub 2018 Dec 11.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, the Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, the Netherlands.

Background: Fluoropyrimidine therapy including capecitabine or 5-fluorouracil can result in severe treatment-related toxicity in up to 30% of patients. Toxicity is often related to reduced activity of dihydropyrimidine dehydrogenase, the main metabolic fluoropyrimidine enzyme, primarily caused by genetic DPYD polymorphisms. In a large prospective study, it was concluded that upfront DPYD-guided dose individualisation is able to improve safety of fluoropyrimidine-based therapy. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S09598049183147
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http://dx.doi.org/10.1016/j.ejca.2018.11.010DOI Listing
January 2019
20 Reads
5.417 Impact Factor

Clinical Value of Pharmacogenomic Testing in a Patient Receiving FOLFIRINOX for Pancreatic Adenocarcinoma.

Front Pharmacol 2018 15;9:1309. Epub 2018 Nov 15.

Department of Hematology and Oncology, Mayo Clinic, Jacksonville, FL, United States.

Pharmacogenomic testing may have clinical value in the treatment of patients with gastrointestinal malignancies such as colorectal and pancreatic cancer. These types of cancer are often treated with combination chemotherapy regimens. These regimens can lead to severe adverse effects in patients with diminished drug tolerability potentially due to certain genetic variants in the enzymes involved in the metabolism of the chemotherapies. Read More

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http://dx.doi.org/10.3389/fphar.2018.01309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249237PMC
November 2018
11 Reads

Effectiveness and safety of reduced-dose fluoropyrimidine therapy in patients carrying the DPYD*2A variant: A matched pair analysis.

Int J Cancer 2019 05 4;144(9):2347-2354. Epub 2019 Jan 4.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

Carriers of the genetic DPYD*2A variant, resulting in dihydropyrimidine dehydrogenase deficiency, are at significantly increased risk of developing severe fluoropyrimidine-associated toxicity. Upfront DPYD*2A genotype-based dose reductions improve patient safety, but uncertainty exists whether this has a negative impact on treatment effectiveness. Therefore, our study investigated effectiveness and safety of DPYD*2A genotype-guided dosing. Read More

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http://dx.doi.org/10.1002/ijc.32022DOI Listing
May 2019
10 Reads
5.085 Impact Factor

Standard fluoropyrimidine dosages in chemoradiation therapy result in an increased risk of severe toxicity in DPYD variant allele carriers.

Eur J Cancer 2018 11 23;104:210-218. Epub 2018 Oct 23.

Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands. Electronic address:

Background: Prospective DPYD genotyping prevents severe fluoropyrimidine (FP)-induced toxicity by decreasing dosages in DPYD variant allele carriers. FP dosages in chemoradiation therapy (CRT) are lower than those in other FP-containing regimens. Pharmacogenetic guidelines do not distinguish between regimens, leaving physicians in doubt to apply dose reductions. Read More

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http://dx.doi.org/10.1016/j.ejca.2018.07.138DOI Listing
November 2018
15 Reads
5.420 Impact Factor

DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis.

Lancet Oncol 2018 11 19;19(11):1459-1467. Epub 2018 Oct 19.

Division of Pharmacology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, Netherlands; Division of Pharmacoepidemiology and Clinical Pharmacology, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Utrecht, Netherlands. Electronic address:

Background: Fluoropyrimidine treatment can result in severe toxicity in up to 30% of patients and is often the result of reduced activity of the key metabolic enzyme dihydropyrimidine dehydrogenase (DPD), mostly caused by genetic variants in the gene encoding DPD (DPYD). We assessed the effect of prospective screening for the four most relevant DPYD variants (DPYD*2A [rs3918290, c.1905+1G>A, IVS14+1G>A], c. Read More

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https://linkinghub.elsevier.com/retrieve/pii/S14702045183068
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http://dx.doi.org/10.1016/S1470-2045(18)30686-7DOI Listing
November 2018
21 Reads
24.690 Impact Factor

Pharmacogenetic analyses of 2183 patients with advanced colorectal cancer; potential role for common dihydropyrimidine dehydrogenase variants in toxicity to chemotherapy.

Eur J Cancer 2018 Oct 13;102:31-39. Epub 2018 Aug 13.

Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK. Electronic address:

Background: Inherited genetic variants may influence response to, and side-effects from, chemotherapy. We sought to generate a comprehensive inherited pharmacogenetic profile for oxaliplatin and 5FU/capecitabine therapy in advanced colorectal cancer (aCRC).

Methods: We analysed more than 200 potentially functional, common, inherited variants in genes within the 5FU, capecitabine, oxaliplatin and DNA repair pathways, together with four rare dihydropyrimidine dehydrogenase (DPYD) variants, in 2183 aCRC patients treated with oxaliplatin-fluoropyrimidine chemotherapy with, or without, cetuximab (from MRC COIN and COIN-B trials). Read More

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http://dx.doi.org/10.1016/j.ejca.2018.07.009DOI Listing
October 2018
63 Reads

A Novel Variant Associated With Severe Toxicity of Fluoropyrimidines: Role of Pre-emptive Genotype Screening.

Front Oncol 2018 24;8:279. Epub 2018 Jul 24.

Department of Clinical Oncology, Queen Mary Hospital, Hong Kong, Hong Kong.

The fluoropyrimidine anticancer drug, especially 5- fluorouracil (5-FU) and its prodrug capecitabine are still being the backbone of chemotherapeutic regimens for colorectal cancer. Dihydropyrimidine dehydrogenase (DPD) is the crucial enzyme in the catabolism of 5-FU. Over the past 30 years, there is substantial clinical evidence showing that DPD deficiency is strongly associated with severe and fatal fluoropyrimidine-induced toxicity. Read More

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http://dx.doi.org/10.3389/fonc.2018.00279DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066555PMC
July 2018
19 Reads

Germline pharmacogenomics of DPYD*9A (c.85T>C) variant in patients with gastrointestinal malignancies treated with fluoropyrimidines.

J Gastrointest Oncol 2018 Jun;9(3):416-424

Medical Oncology, The University of South Alabama, Mitchell Cancer Institute, Mobile, Alabama, USA.

Background: The correlation between DPYD*9A (c.85T>C) genotype and dihydropyrimidine dehydrogenase (DPD) deficiency clinical phenotype is controversial. Reference laboratories either did not perform DPYD*9A genotyping or have stopped DPYD*9A genotyping and limited genotyping to high-risk variants (DPYD*2A, DPYD*13 and DPYD*9B) only. Read More

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http://dx.doi.org/10.21037/jgo.2018.02.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006041PMC
June 2018
42 Reads

Preliminary Evidence for Enhanced Thymine Absorption: A Putative New Phenotype Associated With Fluoropyrimidine Toxicity in Cancer Patients.

Ther Drug Monit 2018 08;40(4):495-502

School of Pharmacy, Pharmacy Australia Center of Excellence, The University of Queensland.

Background: Chemotherapy for colorectal, head and neck, and breast cancer continues to rely heavily on 5-fluorouracil and its oral prodrug capecitabine. Associations of serious fluoropyrimidine adverse effects have focused on inherited deficiency of the catabolic enzyme, dihydropyrimidine dehydrogenase. However, abnormal dihydropyrimidine dehydrogenase activity accounts for only about one-third of observed toxicity cases. Read More

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http://dx.doi.org/10.1097/FTD.0000000000000532DOI Listing
August 2018
44 Reads
2.376 Impact Factor

Come a long way, still a ways to go: from predicting and preventing fluoropyrimidine toxicity to increased efficacy?

Pharmacogenomics 2018 06 22;19(8):689-692. Epub 2018 May 22.

University Institute of Clinical Chemistry, Inselspital Bern University Hospital, University of Bern, Inselspital INO-F, CH-3010 Bern, Switzerland.

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http://dx.doi.org/10.2217/pgs-2018-0040DOI Listing
June 2018
6 Reads

Functional Characterization of 21 Allelic Variants of Dihydropyrimidine Dehydrogenase Identified in 1070 Japanese Individuals.

Drug Metab Dispos 2018 08 16;46(8):1083-1090. Epub 2018 May 16.

Laboratory of Pharmacotherapy of Life-Style Related Diseases, Graduate School of Pharmaceutical Sciences (E.H., Yo.N., F.A., Yu.N., N.H., M.H.), and Tohoku Medical Megabank Organization (S.S., J.Y., M.N., M.Y., M.H.), and Department of Pharmaceutical Sciences, Tohoku University Hospital, Sendai, Japan (M.M., H.Y., N.M., M.H.)

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1. Read More

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http://dx.doi.org/10.1124/dmd.118.081737DOI Listing
August 2018
31 Reads

Assessment of Tumor Sequencing as a Replacement for Lynch Syndrome Screening and Current Molecular Tests for Patients With Colorectal Cancer.

JAMA Oncol 2018 06;4(6):806-813

Department of Laboratory Medicine, University of Washington, Seattle.

Importance: Universal tumor screening for Lynch syndrome (LS) in colorectal cancer (CRC) is recommended and involves up to 6 sequential tests. Somatic gene testing is performed on stage IV CRCs for treatment determination. The diagnostic workup for patients with CRC could be simplified and improved using a single up-front tumor next-generation sequencing test if it has higher sensitivity and specificity than the current screening protocol. Read More

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http://dx.doi.org/10.1001/jamaoncol.2018.0104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5885168PMC
June 2018
40 Reads

Pharmacogenetics of toxicity of 5-fluorouracil, doxorubicin and cyclophosphamide chemotherapy in breast cancer patients.

Oncotarget 2018 Feb 10;9(10):9114-9136. Epub 2018 Jan 10.

Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice, Poland.

The differences in patients' response to the same medication, toxicity included, are one of the major problems in breast cancer treatment. Chemotherapy toxicity makes a significant clinical problem due to decreased quality of life, prolongation of treatment and reinforcement of negative emotions associated with therapy. In this study we evaluated the genetic and clinical risk factors of FAC chemotherapy-related toxicities in the group of 324 breast cancer patients. Read More

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http://dx.doi.org/10.18632/oncotarget.24148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5823653PMC
February 2018
13 Reads

and genotyping to predict adverse events during first-line FOLFIRI or FOLFOXIRI plus bevacizumab in metastatic colorectal cancer.

Oncotarget 2018 Jan 21;9(8):7859-7866. Epub 2017 Dec 21.

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Our study addresses the issue of the clinical reliability of three candidate DPYD and one UGT single nucleotide polymorphisms in predicting 5-fluorouracil- and irinotecan-related adverse events. To this purpose, we took advantage of a large cohort of metastatic colorectal cancer patients treated with first-line 5-fluorouracil- and irinotecan-based chemotherapy regimens (i.e. Read More

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http://dx.doi.org/10.18632/oncotarget.23559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5814264PMC
January 2018
78 Reads

[Dihydropyrimidine déhydrogenase (DPD) deficiency screening and securing of fluoropyrimidine-based chemotherapies: Update and recommendations of the French GPCO-Unicancer and RNPGx networks].

Bull Cancer 2018 Apr 24;105(4):397-407. Epub 2018 Feb 24.

Laboratoire d'oncopharmacologie, centre Antoine-Lacassagne, 33, avenue de Valombrose, 06189 Nice cedex 2, France. Electronic address:

Fluoropyrimidines (FU) are still the most prescribed anticancer drugs for the treatment of solid cancers. However, fluoropyrimidines cause severe toxicities in 10 to 40% of patients and toxic deaths in 0.2 to 0. Read More

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http://dx.doi.org/10.1016/j.bulcan.2018.02.001DOI Listing
April 2018
70 Reads
1 Citation
0.640 Impact Factor

Gene-Specific Variant Classifier (DPYD-Varifier) to Identify Deleterious Alleles of Dihydropyrimidine Dehydrogenase.

Clin Pharmacol Ther 2018 10 2;104(4):709-718. Epub 2018 Feb 2.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

Deleterious variants in dihydropyrimidine dehydrogenase (DPD, DPYD gene) can be highly predictive of clinical toxicity to the widely prescribed chemotherapeutic 5-fluorouracil (5-FU). However, there are very limited data pertaining to the functional consequences of the >450 reported no-synonymous DPYD variants. We developed a DPYD-specific variant classifier (DPYD-Varifier) using machine learning and in vitro functional data for 156 missense DPYD variants. Read More

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http://dx.doi.org/10.1002/cpt.1020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043412PMC
October 2018
25 Reads

Pharmacogenetic landscape of DPYD variants in south Asian populations by integration of genome-scale data.

Pharmacogenomics 2018 02 14;19(3):227-241. Epub 2017 Dec 14.

GN Ramachandran Knowledge Center for Genome Informatics, CSIR Institute of Genomics & Integrative Biology, Mathura Road, Delhi 110025, India.

Aim: Adverse drug reactions to 5-Fluorouracil(5-FU) is frequent and largely attributable to genetic variations in the DPYD gene, a rate limiting enzyme that clears 5-FU. The study aims at understanding the pharmacogenetic landscape of DPYD variants in south Asian populations.

Materials & Methods: Systematic analysis of population scale genome wide datasets of over 3000 south Asians was performed. Read More

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https://www.futuremedicine.com/doi/10.2217/pgs-2017-0101
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http://dx.doi.org/10.2217/pgs-2017-0101DOI Listing
February 2018
31 Reads

DPYD*2A and MTHFR C677T predict toxicity and efficacy, respectively, in patients on chemotherapy with 5-fluorouracil for colorectal cancer.

Cancer Chemother Pharmacol 2018 01 13;81(1):119-129. Epub 2017 Nov 13.

Department of Clinical Pharmacy and Pharmacology, Faculty of Pharmacy, University of Dhaka, Dhaka, 1000, Bangladesh.

Background: Significant inter-individual variation in the sensitivity to 5-fluorouracil (5-FU) represents a major therapeutic hindrance either by impairing drug response or inducing adverse drug reactions (ADRs). This study aimed at exploring the cause behind this inter-individual alterations in consequences of 5-fluorouracil-based chemotherapy by investigating the effects of DPYD*2A and MTHFR C677T polymorphisms on toxicity and response of 5-FU in Bangladeshi colorectal cancer patients.

Methods: Colorectal cancer patients (n = 161) receiving 5-FU-based chemotherapy were prospectively enrolled. Read More

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http://dx.doi.org/10.1007/s00280-017-3478-3DOI Listing
January 2018
41 Reads
2.770 Impact Factor

DPYD genotype-guided dose individualization to improve patient safety of fluoropyrimidine therapy: call for a drug label update.

Ann Oncol 2017 Dec;28(12):2915-2922

Division of Pharmacology.

The fluoropyrimidine anticancer drugs, especially 5-fluorouracil (5-FU) and capecitabine, are frequently prescribed for several types of cancer, including breast, colorectal, head and neck and gastric cancer. In the current drug labels of 5-FU and capecitabine in the European Union and the United States, no adaptive dosing strategies are incorporated for polymorphic metabolism of 5-FU. Although treatment with fluoropyrimidines is generally well tolerated, a major clinical limitation is that a proportion of the treated population experiences severe, sometimes life-threatening, fluoropyrimidine-related toxicity. Read More

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http://dx.doi.org/10.1093/annonc/mdx411DOI Listing
December 2017
17 Reads

Capecitabine-based treatment of a patient with a novel DPYD genotype and complete dihydropyrimidine dehydrogenase deficiency.

Int J Cancer 2018 01 30;142(2):424-430. Epub 2017 Sep 30.

Laboratory Genetic Metabolic Diseases, Departments of Clinical Chemistry and Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Fluoropyrimidines are frequently used anti-cancer drugs. It is known that patients with reduced activity of dihydropyrimidine dehydrogenase (DPD), the key metabolic enzyme in fluoropyrimidine inactivation, are at increased risk of developing severe fluoropyrimidine-related toxicity. Upfront screening for DPD deficiency and dose reduction in patients with partial DPD deficiency is recommended and improves patient safety. Read More

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http://dx.doi.org/10.1002/ijc.31065DOI Listing
January 2018
37 Reads

P53 represses pyrimidine catabolic gene dihydropyrimidine dehydrogenase (DPYD) expression in response to thymidylate synthase (TS) targeting.

Sci Rep 2017 08 29;7(1):9711. Epub 2017 Aug 29.

Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA, 19111, USA.

Nucleotide metabolism in cancer cells can influence malignant behavior and intrinsic resistance to therapy. Here we describe p53-dependent control of the rate-limiting enzyme in the pyrimidine catabolic pathway, dihydropyrimidine dehydrogenase (DPYD) and its effect on pharmacokinetics of and response to 5-fluorouracil (5-FU). Using in silico/chromatin-immunoprecipitation (ChIP) analysis we identify a conserved p53 DNA-binding site (p53BS) downstream of the DPYD gene with increased p53 occupancy following 5-FU treatment of cells. Read More

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http://dx.doi.org/10.1038/s41598-017-09859-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5575263PMC
August 2017
36 Reads

Use of exome sequencing to determine the full profile of genetic variants in the fluoropyrimidine pathway in colorectal cancer patients affected by severe toxicity.

Pharmacogenomics 2017 Aug 26;18(13):1215-1223. Epub 2017 Jul 26.

Instituto de Investigación Sanitaria Gregorio Marañón, Hospital General Universitario Gregorio Marañón, Madrid, Spain.

Aim: To identify genetic variants associated with capecitabine toxicity in fluoropyrimidine pathway genes using exome sequencing.

Patients & Methods: Exomes from eight capecitabine-treated patients with severe adverse reactions (grade >2), among a population of 319, were sequenced (Ion Proton). SNPs in genes classified as potentially damaging (Sorting Intolerant from Tolerant and Polymorphism Phenotyping v2) were tested for association with toxicity in a validation cohort of 319 capecitabine-treated patients. Read More

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http://dx.doi.org/10.2217/pgs-2017-0118DOI Listing
August 2017
30 Reads

Low Incidence of the DPD IVS14+1G>A Polymorphism in Jordanian Breast and Colorectal Cancer patients

Asian Pac J Cancer Prev 2017 06 25;18(6):1651-1654. Epub 2017 Jun 25.

Thrombosis Haemostasis Laboratory, University of Jordan, Amman, Jordan.

Background: Dihydropyrimidine dehydrogenase (DPD) is a crucial enzyme in the catabolism of 5-fluorouracil (5-FU), a drug that is frequently used in cancer therapy. Patients with deficient DPD activity are at risk of developing severe 5-FU–associated toxicity. One possible cause of deficiency is genetic polymorphisms in the DPD gene, such as IVS14+1G>A. Read More

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http://dx.doi.org/10.22034/APJCP.2017.18.6.1651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6373818PMC
June 2017
22 Reads

Letter regarding Zhao et al. entitled " DPYD gene polymorphisms are associated with risk and chemotherapy prognosis in pediatric patients with acute lymphoblastic leukemia".

Tumour Biol 2017 06;39(6):1010428317701629

6 Dutch Medicines Evaluation Board (CBG-MEB), Utrecht, The Netherlands.

Zhao et al. investigated the association between germline genetic polymorphisms in DPYD, the gene encoding dihydropyrimidine dehydrogenase, and (1) the risk of developing pediatric acute lymphoblastic leukemia and (2) outcome of acute lymphoblastic leukemia following the treatment with 5-fluorouracil plus oxaliplatin (FOLFOX). The authors found that the common DPYD variant c. Read More

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http://dx.doi.org/10.1177/1010428317701629DOI Listing
June 2017
45 Reads

Fluoropyrimidine-Associated Toxicity in Two Gastrointestinal Cancer Patients: Potential Role of Common DPYD Polymorphisms.

Chemotherapy 2017 15;62(5):323-326. Epub 2017 Jun 15.

Unit of Clinical Pharmacology, Department of Laboratory Medicine, ASST Fatebenefratelli-Sacco, Milan, Italy.

While the majority of patients can be treated safely with fluoropyrimidine, some experience severe fluoropyrimidine-associated toxicity. The frequency and severity of these adverse events vary from patient to patient and are partially explained by genetic polymorphism into the dihydropyrimidine dehydrogenase (DPYD) gene. Carriers of the rare allelic variants DPYD*2A, DPYD*13, and DPYD D949V are more likely to experience severe adverse reactions during fluoropyrimidine-based therapy. Read More

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https://www.karger.com/Article/FullText/477333
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http://dx.doi.org/10.1159/000477333DOI Listing
September 2017
17 Reads

New advances in DPYD genotype and risk of severe toxicity under capecitabine.

PLoS One 2017 8;12(5):e0175998. Epub 2017 May 8.

Centre Antoine Lacassagne, Nice, France.

Background: Deficiency in dihydropyrimidine dehydrogenase (DPD) enzyme is the main cause of severe and lethal fluoropyrimidine-related toxicity. Various approaches have been developed for DPD-deficiency screening, including DPYD genotyping and phenotyping. The goal of this prospective observational study was to perform exhaustive exome DPYD sequencing and to examine relationships between DPYD variants and toxicity in advanced breast cancer patients receiving capecitabine. Read More

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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0175998PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421769PMC
September 2017
131 Reads
1 Citation
3.234 Impact Factor

Pretreatment serum uracil concentration as a predictor of severe and fatal fluoropyrimidine-associated toxicity.

Br J Cancer 2017 May 20;116(11):1415-1424. Epub 2017 Apr 20.

Department of Clinical Pharmacology, Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands.

Background: We investigated the predictive value of dihydropyrimidine dehydrogenase (DPD) phenotype, measured as pretreatment serum uracil and dihydrouracil concentrations, for severe as well as fatal fluoropyrimidine-associated toxicity in 550 patients treated previously with fluoropyrimidines during a prospective multicenter study.

Methods: Pretreatment serum concentrations of uracil and dihydrouracil were measured using a validated LC-MS/MS method. The primary endpoint of this analysis was global (any) severe fluoropyrimidine-associated toxicity, that is, grade ⩾3 toxicity according to the NCI CTC-AE v3. Read More

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http://dx.doi.org/10.1038/bjc.2017.94DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520099PMC
May 2017
59 Reads

Identification of new SNPs associated with severe toxicity to capecitabine.

Pharmacol Res 2017 Jun 27;120:133-137. Epub 2017 Mar 27.

Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Madrid, Spain. Electronic address:

Predicting individual risk of chemotherapy-induced severe adverse reaction is a critical issue when selecting the best treatment for cancer patients. SNPs have been identified in genes involved in the pharmacodynamics of fluoropyrimidines, and guidelines even recommend genotyping some DPYD variants in order to estimate the risk of toxicity. However, the predictive value of this approach remains insufficient, thus limiting its clinical implementation. Read More

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http://dx.doi.org/10.1016/j.phrs.2017.03.021DOI Listing
June 2017
16 Reads

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient.

Anticancer Drugs 2017 06;28(5):551-556

Departments of aClinical and Molecular Medicine bRadiological Oncological and Pathological Sciences cNeurosciences, Mental Health and Sensory Organs (NESMOS), 'Sapienza' University of Rome dDepartment of Medical Oncology, Sant'Andrea Hospital eLaboratory of Medical Physics and Expert Systems, Regina Elena National Cancer Institute fIstituto Dermopatico dell'Immacolata-IRCCS, Rome, Italy.

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients' characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Read More

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http://dx.doi.org/10.1097/CAD.0000000000000492DOI Listing
June 2017
32 Reads

Quantitative Contribution of rs75017182 to Dihydropyrimidine Dehydrogenase mRNA Splicing and Enzyme Activity.

Clin Pharmacol Ther 2017 Oct 26;102(4):662-670. Epub 2017 May 26.

Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.

Dihydropyrimidine dehydrogenase (DPD; DPYD gene) variants have emerged as reliable predictors of adverse toxicity to the chemotherapy agent 5-fluorouracil (5-FU). The intronic DPYD variant rs75017182 has been recently suggested to promote alternative splicing of DPYD. However, both the extent of alternative splicing and the true contribution of rs75017182 to DPD function remain unclear. Read More

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http://dx.doi.org/10.1002/cpt.685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6138243PMC
October 2017
12 Reads

Pharmacogenetics and Metabolism from Science to Implementation in Clinical Practice: The Example of Dihydropyrimidine Dehydrogenase.

Curr Pharm Des 2017 ;23(14):2028-2034

Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.

Background: Fluoropyrimidines are widely used in the treatment of solid tumors and remain the backbone of many combination chemotherapy regimens. Despite their clinical benefit, they are associated with frequent gastrointestinal and hematological toxicities, which often lead to treatment discontinuation. Fluoropyrimidines undergo complex anabolic and catabolic biotransformation. Read More

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http://dx.doi.org/10.2174/1381612823666170125155530DOI Listing
April 2018
26 Reads