Pharmacogenetic Variants Can Influence Optical Medication Use.

INTRODUCTION: Single Nucleotide Polymorphisms (SNPs) are used as drug susceptibility biomarkers in metabolic diseases. Alterations in the gene encoding triggers the enzyme flavin monooxygenase 3 (FMO3), involved in the Sulindac metabolization, which also is responsible for the inherited metabolic disorder. Trimethylaminuria (TMAu, OMIM: 602079). DPYD gene variants are associated with the enzyme dihydropyrimidine dehydrogenase deficiency (DPD; OMIM: 274270). This autosomal recessive metabolic disorder, ultimately leads to the inability to metabolize fluoropyrimidines, which causes severe toxicity in individuals treated with these drugs. METHODS: Variants in genes responsible for the expression of enzymes that encode transporters or receptors involved in the metabolization pathways of certain drugs may condition the individuals response to certain drugs, compromising the therapeutic response and clinical prognosis. Thus the sequencing and identification of variants become relevant, not only gain knowledge on effects of these variants' on disease causality but also in terms of its side effects resulting from the coding enzymes responsible for drug metabolization. RESULTS: It was found that patients with the c.472G>A (p.Glu158Lys) and c.923A>G (p.Glu308Gly) polymorphisms, in homozygosity, in FMO3 gene did not develop polyps, thus have a protective effect in the treatment of Familial Adenomatous Polyposis (PAF). However, in the case of the DPYD gene, c.1905+1G>A (IVS14+1G>A), c.1679T>G (p.Ile560Ser), c.2846A>T (p.Asp949Val) e c.1236G>A/HapB3 variants can be lethal in cancer patients indicated for fluoropyrimidine-based chemotherapy. CONCLUSION: Knowledge on the drug mechanisms will affect the therapeutic response of patients treated with a given drug. Thus, pharmacogenetics is an essential tool in personalized medicine, since molecular studies allows the clinician to predict the probability of efficacy and toxicity of certain drugs, resulting higher efficiency in individualizing treatment and also improving the safety of the patient. From a personalized medicine perspective, the study of the characteristics of the drug and its metabolization site, the genes involved in the encoding of enzymes responsible for its metabolization will be of great interest.

The Incidence of Hematological Toxicities in Colorectal Cancer Patients Treated With Fluoropyrimidine-Based Regimens at Princess Noorah Oncology Center.

Background Fluoropyrimidine-based regimens are used for the management of colorectal cancer, which is the second most common cancer in Saudi Arabia. We aimed to study the incidence of hematological toxicities in colorectal cancer patients treated with fluoropyrimidine and fluoropyrimidine-based regimens at Princess Noorah Oncology Center, King Abdulaziz Medical City- Jeddah, Saudi Arabia.  Methods A retrospective cohort study that included adult colorectal cancer patients who were treated with fluoropyrimidine-based regimens from January 1, 2018 to December 31, 2018 at Princess Noorah Oncology Center, Jeddah, Saudi Arabia was performed. Our primary objective was to determine the incidence of anemia, neutropenia, and thrombocytopenia in colorectal cancer patients treated with fluoropyrimidines and fluoropyrimidine-based regimens. Secondary objectives were to assess the grade of hematological toxicities associated with 5-fluorouracil (5-FU) use and to determine the frequency of unplanned hospital admissions or emergency department (ED) visits after receiving fluoropyrimidine-based regimens. The collected data contained patients' characteristics (weight, height, age, gender, and diagnosis), chemotherapy agents, and hematological toxicity-related findings such as absolute neutrophil count, hemoglobin, platelet count, and number of ED visits or hospital admissions during fluoropyrimidine-based chemotherapy regimens. Results Of the 570 cycles of the fluoropyrimidine-based regimen received by 68 patients, hematological toxicities were observed in 508 (89.1%) cycles, and grade ≥ 3 grade toxicities were found in 46 (8.1%) cycles. The results demonstrated a statistically significant difference in the incidence of grade 3-4 neutropenia between patients who received bolus administration of 5-FU and those who did not (8.5% vs. 2.3% respectively, p=0.025). The incidence of grade 3-4 anemia was higher in the bolus group (11.3%) compared to the group where bolus was omitted (4.6%); however, the difference was not statistically significant (p=0.059). Furthermore, there was no significant difference among the two groups for grade 3 and grade 4 thrombocytopenia (0.0% with bolus given and 0.7% with bolus omission p=1.00). Conclusion Our retrospective study showed that there have been significantly higher grade 3-4 hematological toxicities observed with bolus administration of 5-FU, which confirms the previous reports.

Renal impairment and abnormal liver function tests in pre-therapeutic phenotype-based DPD deficiency screening using uracilemia: a comprehensive population-based study in 1138 patients.

Background: Dihydropyrimidine dehydrogenase (DPD) deficiency screening is a pre-therapeutic standard to prevent severe fluoropyrimidine-related toxicity. Although several screening methods exist, the accuracy of their results remains debatable. In France, the uracilemia measurement is considered the standard in DPD deficiency screening. The objective of this study was to describe the hyperuracilemia (⩾16 ng/mL) rate and investigate the influence of hepatic and renal impairment in uracilemia measurements since the guidelines were implemented. Patients and methods: Using a cohort of 1138 patients screened between 18 October 2018 and 18 October 2021, basic demographic characteristics, date of blood sampling, and potential biological confounders including liver function tests [aspartate aminotransaminase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transferase (γGT), alkaline phosphatase (ALP), and bilirubin] and estimated glomerular filtration rate (eGFR) were collected. The second same-patient uracilemia analysis was also performed. Temporal change was graphically represented while potential confounders were stratified to show linearity when suspected. Results: Hyperuracilemia was diagnosed in 12.7% (n = 150) samples with 6.7%, 5.4%, 0.5%, and 0.08% between 16 and 20 ng/mL, 20 and 50 ng/mL, 50 and 150 ng/mL, and >150 ng/mL, respectively. The median uracilemia concentration was 9.4 ng/mL (range: 1.2 and 172.3 ng/mL) and the monthly hyperuracilemia rate decreased steadily from >30% to around 9%. Older age, normalized AST, γGT, ALP results, bilirubin levels, and decreased eGFR were linearly associated with higher plasma uracil concentrations (all p < 0.001). In the adjusted multivariate linear model, AST, eGFR, and ALP remained associated with uracilemia (p < 0.05). When measured twice in 39 patients, the median uracilemia rate of change was -2.5%, which subsequently changed the diagnosis in nine patients (23.1%). Conclusions: Better respect of pre-analytical conditions may explain the steady decrease in monthly hyperuracilemia rates over the 3 years. Elevated AST, ALP levels, and reduced eGFR could induce a false increase in uracilemia and second uracilemia measurements modified the first DPD deficiency diagnosis in almost 25% of the patients.

DPYD Exon 4 Deletion Associated with Fluoropyrimidine Toxicity and Importance of Copy Number Variation.

Fluoropyrimidine chemotherapy is associated with interpatient variability in toxicity. A major contributor to unpredictable and severe toxicity relates to single nucleotide variation (SNV) in dihydropyrimidine dehydrogenase (DPYD), the rate-limiting fluoropyrimidine metabolizing enzyme. In addition to SNVs, a study of Finnish patients suggested that a DPYD exon 4 deletion was observed in their population. To better understand the potential generalizability of such findings, we investigated the presence of this exon 4 deletion in our Canadian patient population, using a TaqMan assay. We selected 125 patients who experienced severe fluoropyrimidine-associated toxicity, and 125 matched controls. One patient in the severe toxicity group harbored a haploid DPYD exon 4 deletion, and required a 35% dose reduction after their first fluoropyrimidine treatment cycle due to toxicity and required an additional 30% dose reduction before tolerating treatment. The predicted allele frequency was 0.2% in our cohort, much lower than the 2.4% previously reported. We also carried out a literature review of copy number variation (CNV) in the DPYD gene, beyond fluoropyrimidine toxicity and show that various types of CNV in DPYD are present in the population. Taken together, our findings suggest that CNV in DPYD may be an underappreciated determinant of DPYD-mediated fluoropyrimidine toxicity.

5-Fluorouracil Neurotoxicity in a Patient With Normal Dihydropyrimidine Dehydrogenase Activity.

5-fluorouracil (5-FU) is a well-known chemotherapeutic agent used for the treatment of colon cancer and other solid malignancies. Dihydropyrimidine dehydrogenase (DPD) is an enzyme that catalyzes 5-FU, and if a patient is deficient, such as through a gene mutation, they can be predisposed to severe toxicity. Although 5-FU-induced neurotoxicity is extremely rare, it can be fatal. We report a case of 5-FU neurotoxicity in a 56-year-old male patient with keratinizing squamous cell carcinoma of the anal canal on concurrent chemoradiation therapy consisting of 5-FU, mitomycin, and radiotherapy. Encephalopathy, dysarthria, and ataxia were noted on day three of treatment. MRI of the brain showed a pattern of global anoxic brain injury. DPD testing was negative for polymorphism, and the patient's symptoms improved after treatment with uridine triacetate, the treatment for 5-FU toxicity.

Eritrodisestesia palmoplantar tras tratamiento perioperatorio con quimioterapia / Palmoplantar erythrodysesthesia after perioperative treatment with chemotherapy

La eritrodisestesia palmoplantar es una reacción adversa que se asocia a la administración de docetaxel y fluoropirimidinas. La actividad de la enzima dihidropirimidina deshidrogenasa (DPD) determina la tasa de catabolismo del 5-Fluorouracilo (5-FU) y está sujeta a variabilidad interindividual y polimorfismo genético. Por tanto, los pacientes con deficiencia de DPD presentan un mayor riesgo de toxicidad. Presentamos el caso de un paciente tratado con docetaxel, oxaliplatino y 5-FU (esquema FLOT) que presentó toxicidad cutánea moderada y del que se sospechó deficiencia de DPD.(AU)

Palmoplantar erythrodysesthesia is an adverse event associated with the administration of docetaxel and fluoropyrimidines. The activity of the enzyme dihydropyrimidine dehydrogenase (DPD) determines the rate of catabolism of 5-Fluorouracil (5-FU) and is subject to interindividual variability and genetic polymorphism. Therefore, patients with DPD deficiency present an increased risk of toxicity. We present the case of a patient treated with docetaxel, oxaliplatin and 5-FU (FLOT scheme) who presented moderate skin toxicity and who was suspected of DPD deficiency.(AU)

Impact of Guidelines Regarding Dihydropyrimidine Dehydrogenase (DPD) Deficiency Screening Using Uracil-Based Phenotyping on the Reduction of Severe Side Effect of 5-Fluorouracil-Based Chemotherapy: A Propension Score Analysis.

Dihydropyrimidine dehydrogenase (DPD) deficiency is associated with severe fluoropyrimidines-induced toxicity. As of September 2018, French recommendations call for screening for DPD deficiency by plasma uracil quantification prior to all fluoropyrimidine-based chemotherapy. A dose reduction of fluoropyrimidine is recommended when uracil concentration is equal to or greater than 16 ng/mL. This matched retrospective study assessed the impact of DPD screening on the reduction of severe side effects and on the management of DPD-deficient patients. Using a propensity score, we balanced the factors influencing 5-Fluorouracil (5-FU) toxicity. Then, the severity scores (G3 and G4 severity as well as their frequency) of patients who did not benefit from DPD screening were compared with those of patients who benefited from DPD screening for each treatment cycle (from 1 to 4). Among 349 screened patients, 198 treated patients were included. Among them, 31 (15.7%) had DPD deficiency (median uracilemia 19.8 ng/mL (range: 16.1−172.3)). The median toxicity severity score was higher in the unscreened group for each treatment cycle (0 vs. 1, p < 0.001 at each cycle from 1 to 4) as well as the cumulative score during all courses of treatment (p = 0.028). DPD-deficient patients received a significantly lower dose of 5-FU (p < 0.001). This study suggests that pretherapeutic plasmatic uracil assessment, along with 5-FU dosage adjustment, may be beneficial in reducing 5-FU toxicity in real-life patients.

Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants. MATERIALS AND METHODS: We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model. RESULTS: Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%. CONCLUSION: Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death. IMPLICATIONS FOR PRACTICE: The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.

Real-world Safety and Efficacy of Raltitrexed in Patients With Metastatic Colorectal Cancer.

BACKGROUND: Use of fluoropyrimidine-based therapy in patients with metastatic colorectal cancer is associated with significant toxicities. This study aimed to assess the safety and efficacy of raltitrexed use in patients with metastatic colorectal cancer who developed significant toxicities after fluoropyrimidine-based treatment. PATIENTS AND METHODS: We identified patients with metastatic colorectal cancer who were treated with raltitrexed-based systemic therapy after developing serious adverse events with fluoropyrimidine-based treatment in a large Canadian province from 2004 to 2018. Demographic, tumor, and treatment characteristics were retrieved from the electronic medical records. Progression-free and overall survival were assessed from the start of raltitrexed-based therapy. RESULTS: A total of 86 patients were identified for the study. The median age was 66.5 years, and 58.1% of patients were men. The primary cancer site was right, left, and transverse colon in 38.4%, 27.9%, and 9.3%, respectively. The remaining 24.4% had rectal cancer. Among all patients, 43.0% had received more than 2 prior systemic therapies, and 37.6% had developed previous cardiotoxicity to fluoropyrimidine-based treatment. The median progression-free and overall survival were 8.5 and 10.2 months, respectively. On multivariable Cox regression model, patients with left-sided colon cancer (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.12-0.97; P = .044) and the Eastern Cooperative Oncology Group performance status of 0/1 (HR, 0.10; 95% CI, 0.01-0.82; P = .032) had a longer progression-free survival, whereas left-sidedness of colon cancer was the only factor that predicted overall survival (HR, 0.30; 95% CI, 0.10-0.88; P = .029). Raltitrexed was well-tolerated with common adverse events that included anemia in 41.7% of patients and chemotherapy-induced nausea and vomiting in 27.4%. Most toxicities were grade 1/2, but 16.7% of patients experienced grade 3. There were no cardiac events and treatment-related deaths. CONCLUSIONS: Raltitrexed in patients with colorectal cancer who were previously treated with fluoropyrimidine-based systemic therapy is effective and well-tolerated.

Frecuencia y relevancia clínica de las variantes del gen DPYD en pacientes con tumores digestivos / Frequency and clinical relevance of DPYD genetic variants in gastrointestinal cancer patients

Objetivo: Determinar la prevalencia de variantes de pérdida de funciónen el gen de la dihidropirimidina deshidrogenasa (DPYD) en pacientescon tumores digestivos, valorar su relevancia clínica y evaluar la implementación de un circuito multidisciplinar tras tres meses de funcionamiento.Método: Estudio descriptivo, observacional y retrospectivo donde seincluyeron los pacientes adultos afectos de tumores digestivos, atendidosen un hospital universitario de tercer nivel, a los que se había efectuado elgenotipado de DPYD entre septiembre de 2019 y diciembre de 2020. Lasvariables recogidas fueron sexo, edad, tipo de cáncer, localización, estadio, tratamiento recibido, indicación del tratamiento y grado de toxicidaddesarrollado durante los tres primeros ciclos. Se genotiparon las variantesrs3918290 (c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798(c.2846A>T) y rs75017182 (c.1129-5923C>G).Resultados: Se incluyeron 115 pacientes. La frecuencia de portadoresen heterocigosis de variantes del gen DPYD fue del 9,6% (11 pacientes).La variante más frecuentemente identificada fue el rs75017182 (6 pacientes). La segunda variante más frecuente fue el rs67376798 (3 pacientes),seguida del rs3918290 (2 pacientes). Ningún paciente presentó la varianters55886062. (AU)

Objective: To determine the prevalence of loss-of-function variants in thedihydropyrimidine dehydrogenase gene in patients with gastrointestinalneoplasms, assess their clinical relevance, and evaluate the implementation of a multidisciplinary circuit at three months from its implementation.Method: This is a descriptive, observational and retrospective study,which included adult patients with gastrointestinal cancer treated at atertiary university hospital who underwent dihydropyrimidine dehydrogenase genotyping between September 2019 and December 2020.The variables collected were sex, age, type of cancer, location, stage,treatment received, indication of treatment and degree of toxicity developed during the first three cycles. The genotyped variants were rs3918290(c.1905+1G>A), rs55886062 (c.1679T>G), rs67376798 (c.2846A>T)and rs75017182 (c.1129-5923C>G).Results: A total of 115 patients were included. The frequency of heterozygous dihydropyrimidine dehydrogenase variant carriers was 9.6%(11 patients). The most frequently identified variant was rs75017182 (6 patients).The second most common variant was rs67376798 (3 patients), followedby rs3918290 (2 patients). No patients presented with the rs55886062variant. (AU)

A Japanese Patient with Gastric Cancer and Dihydropyrimidine Dehydrogenase Deficiency Presenting with DPYD Variants.

A 63-year-old Japanese male with stomach adenocarcinoma received oral 5-fluorouracil derivative, cisplatin and trastuzumab chemotherapy. On day 8, severe diarrhea and mucositis developed; chemotherapy was stopped. On day 14, the patient developed renal dysfunction and febrile neutropenia. He also suffered from pneumonia due to Candida albicans. Systemic symptoms improved after intensive conservative treatment. Best supportive care was continued until the patient died from gastric cancer. The dihydropyrimidine dehydroge-nase protein level was low at 3.18 U/mg protein. The result of DPYD genotyping revealed three variants at posi-tions 1615 (G > A), 1627 (A > G), and 1896 (T > C) in exons 13, 13, and 14, respectively.

Fluoropyrimidine-induced toxicity and DPD deficiency.. A case report of early onset, lethal capecitabine-induced toxicity and mini review of the literature. Uridine triacetate: Efficacy and safety as an antidote. Is it accessible outside USA?

Fluoropyrimidine-based regimens are among the most commonly used chemotherapy combinations for the treatment of solid tumors. Several genetic polymorphisms that are implicated with fluoropyrimidine anabolism and catabolism have been associated with the development of life-threatening toxicities. Uridine triacetate is an FDA-approved antidote for 5-fluorouracil or capecitabine overdose and early-onset, life-threatening toxicity within 96 h of last chemotherapy dose. To date, it is not accessible for Greek patients as per the current summary of product characteristic's time restrictions. We report and discuss the course and outcome of capecitabine toxicity in a 66-year-old female colorectal cancer patient with heterozygous dihydropyrimidine dehydrogenase deficiency. This paper highlights the difficulty in timely access of this lifesaving medication for Greek and possibly other European patients.

Dihydropyrimidine dehydrogenase deficiency as a cause of fatal 5-Fluorouracil toxicity

5-Fluorouracil (5-FU), in combination with other cytotoxic drugs, is commonly used to treat a variety of cancers. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite. Approximately 0.3% of the population demonstrate complete DPD deficiency, translating to extreme toxicity of 5-FU. Here we present a case of a patient who had a fatal outcome after treatment with 5-FU who was found to have an unknown DPD deficiency discovered at autopsy.

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

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. Our aim was to investigate severe toxicity in DPYD variant allele carriers receiving CRT. METHODS: Medical records of 828 patients who received FP-based CRT were reviewed from three centres. Severe (grade ≥III) toxicity in DPYD variant allele carriers receiving upfront FP dose reductions according to pharmacogenetic dosing guidelines and DPYD variant allele carriers not receiving FP dose reductions was compared with DPYD wild-type patients receiving standard dose of FPs in CRT. RESULTS: DPYD variant allele carriers treated with standard dosages (N = 34) showed an increased risk of severe gastrointestinal (adjusted OR = 2.58, confidence interval [CI] = 1.02-6.53, P = 0.045) or severe haematological (adjusted OR = 4.19, CI = 1.32-13.25, P = 0.015) toxicity compared with wild-type patients (N = 771). DPYD variant allele carriers who received dose reductions (N = 22) showed a comparable frequency of severe gastrointestinal toxicity compared with wild-type patients, but more (not statistically significant) severe haematological toxicity. Hospitalisations for all DPYD variant allele carriers were comparable, independent of dose adjustments; however, the mean duration of hospitalisation was significantly shorter in the dose reduction group (P = 0.010). CONCLUSIONS: Standard FP dosages in CRT resulted in an increased risk of severe toxicity in DPYD variant allele carriers. We advise to apply FP dose reductions according to current guidelines in DPYD variant allele carriers starting CRT.

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

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 DPYD gene, 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. There have been several published case reports about DPD deficiency in patients with colorectal cancer in Western countries. However, case reports of DPD deficiency in Japanese patients with colorectal cancer are rare because measuring DPD activity is not covered by public medical insurance in Japan, and it is not examined in our daily clinical practice currently. Therefore, we think that it is important to accumulate such case reports for further understanding. This report describes the case of a Japanese patient with colon cancer who experienced severe side effects while taking capecitabine, due to DPD deficiency. A 68-year-old man with ascending colon cancer underwent curative laparoscopic right hemicolectomy. Because final pathologic staging was Stage IIIa, standard adjuvant chemotherapy with capecitabine (3600 mg/body/day, days 1-14, every 3 weeks) was started on postoperative day 50. After 2 weeks, he started to experience Grade 3 diarrhea and was admitted to the hospital on postoperative day 66. On day 70, the patient had Grade 4 febrile neutropenia. Antibiotics and granulocyte-colony-stimulating factor were administered until his blood tests recovered to the normal degree. After 1 week of diarrhea, antidiarrheal agents were administered, and the patient gradually recovered. During the occurrence of diarrhea, specimen cultures were negative for infection. He was discharged on day 21 of the hospital stay. DPD deficiency was suspected, and 2 weeks later the DPD activity of the peripheral blood mononucleocytes was examined. The result was 10.3 U/mg protein which was remarkedly low (reference range 22.6-183.6 U/mg protein), and DPD deficiency was diagnosed. We always must consider the possibility of DPD deficiency in patients who experience severe side effects while taking capecitabine.

Dihydropyrimidine dehydrogenase deficiency as a cause of fatal 5-Fluorouracil toxicity.

5-Fluorouracil (5-FU), in combination with other cytotoxic drugs, is commonly used to treat a variety of cancers. Dihydropyrimidine dehydrogenase (DPD) catalyzes the first catabolic step of the 5-FU degradation pathway, converting 80% of 5-FU to its inactive metabolite. Approximately 0.3% of the population demonstrate complete DPD deficiency, translating to extreme toxicity of 5-FU. Here we present a case of a patient who had a fatal outcome after treatment with 5-FU who was found to have an unknown DPD deficiency discovered at autopsy.

Molecular basis of 5-fluorouracil-related toxicity: lessons from clinical practice.

We aim to present a comprehensive review of the molecular basis of 5-fluorouracil (5-FU) toxicity, of which dihydropyrimidine dehydrogenase (DYPD) deficiency is a well-known mechanism. The prevalence of partial DYPD deficiency is fairly common, ranging between 3-5% in the general population, whereas it can be as high as 12% in African-American females. More than 50 genetic polymorphisms have been described as being associated with decreased enzymatic activity, whereas the c.1905+1G>A point mutation is the most commonly found (52% of cases), with a prevalence of heterozygosity in the general population ranging between 1-2%. Several methods have been utilized to identify reduced DYPD activity; functional tests are expensive and only available in specialized centers. Genotyping alone is not reliable enough, as some of the polymorphisms may not result in significantly reduced DYPD activity. The rate of cardiotoxicity associated with 5-FU or capecitabine does not seem to be related to DYPD deficiency, and has been estimated to range between 1.2-8%. Several pathophysiological mechanisms seem to contribute to 5-FU cardiotoxicity, including coronary spasm, increased endothelial thrombogenicity and myocardial inflammation. Tegafur/uracil and raltitrexed may be alternative options for patients with partial DYPD deficiency and previous manifested 5-FU cardiotoxicity, respectively. Pharmacogenetics is expected to further identify and clarify the mechanisms associated with 5-FU-related toxicity, thus aiding the oncology societies to formulate specific guidance on pre-treatment testing.

Dihydropyrimidine dehydrogenase deficiency in two malaysian siblings with abnormal MRI findings.

Dihydropyrimidine dehydrogenase (DPD) deficiency is an autosomal recessive disorder of the pyrimidine metabolism. Deficiency of this enzyme leads to an accumulation of thymine and uracil and a deficiency of metabolites distal to the catabolic enzyme. The disorder presents with a wide clinical spectrum, ranging from asymptomatic to severe neurological manifestations, including intellectual disability, seizures, microcephaly, autistic behavior, and eye abnormalities. Here, we report on an 11-year-old Malaysian girl and her 6-year-old brother with DPD deficiency who presented with intellectual disability, microcephaly, and hypotonia. Brain MRI scans showed generalized cerebral and cerebellar atrophy and callosal body dysgenesis in the boy. Urine analysis showed strongly elevated levels of uracil in the girl and boy (571 and 578 mmol/mol creatinine, respectively) and thymine (425 and 427 mmol/mol creatinine, respectively). Sequence analysis of the DPYD gene showed that both siblings were homozygous for the mutation c.1651G>A (pAla551Thr).

Tegafur-uracil is a safe alternative for the treatment of colorectal cancer in patients with partial dihydropyrimidine dehydrogenase deficiency: a proof of principle.

OBJECTIVE: The objective of this study was to evaluate the safety of using tegafur-uracil (UFT) in colorectal cancer patients with partial dihydropyrimidine dehydrogenase (DPD) deficiency. PATIENTS AND METHODS: The study included five colorectal cancer patients who presented with acute toxicity (grades 3 and 4) after being given the first cycle of chemotherapy using 5-fluorouracil. The DPD deficiency was confirmed by gene sequencing. After a full recovery from all side effects, we changed the regimen to UFT (300 mg/m(2)/day) associated with leucovorin (90 mg/day) for 21 days, with an empirical dose reduction of at least 10% in the first cycle. RESULTS: We prospectively analysed 22 UFT cycles in 5 patients. We did not observe any episodes of grade 3 or 4 toxicity. The predominant toxicities were of grades 1 and 2 (nausea, vomiting and diarrhoea). CONCLUSION: Here, we demonstrate a complete absence of severe toxicity in all patients and cycles analysed. We believe that UFT is a safe alternative for the treatment of patients with partial DPD deficiency.