Treatment with Rasburicase in Hospitalized Patients with Cardiorenal Syndrome: Old Treatment, New Scenario.

Cardiorenal syndrome (CRS) involves joint dysfunction of the heart and kidney. Acute forms share biochemical alterations like hyperuricaemia (HU) with tumour lysis syndrome (TLS). The mainstay treatment of acute CRS with systemic overload is diuretics, but rasburicase is used in TLS to prevent and treat hyperuricaemia. An observational, retrospective study was performed to assess the effectiveness and safety of a single dose of rasburicase in hospitalized patients with cardiorenal syndrome, worsening renal function and uric acid levels above 9 mg/dL. Rasburicase improved diuresis and systemic congestion in the 35 patients included. A total of 86% of patients did not need to undergo RRT, and early withdrawal was possible in the remaining five. Creatinine (Cr) decreased after treatment with rasburicase from a peak of 3.6 ± 1.27 to 1.79 ± 0.83 mg/dL, and the estimated glomerular filtration rate (eGFR) improved from 17 ± 8 to 41 ± 20 mL/min/1.73 m2 (p = 0.0001). The levels of N-terminal type B Brain Natriuretic Peptide (Nt-ProBNP) and C-reactive protein (CRP) were also significantly reduced. No relevant adverse events were detected. Our results show that early treatment with a dose of rasburicase in patients with CRS and severe HU is effective to improve renal function and systemic congestion, avoiding the need for sustained extrarenal clearance, regardless of comorbidities and ventricular function.

Medication guide for dose adjustment and management of cardiotoxicity and lipid metabolic adverse events of oral antineoplastic therapy.

Objective: The management of cardiotoxicity concerning the use of oral antineoplastic agents (OAAs) is a challenge for healthcare professionals. Our objective was to create a comprehensive medication management guide with dose adjustment recommendations on OAAs concerning cardiotoxic and lipid metabolic adverse events (AEs) to assist healthcare professionals when prescribing OAAs. Materials and methods: A review of the available information on all dose adjustments necessary to safely prescribe and dispense OAAs concerning cardiotoxicity was conducted. In January 2023, we identified all OAAs authorized by the European Medicines Agency (EMA). For each drug, the latest summary of product characteristics (SPC) approved by the EMA and the tertiary data source Lexicomp® were reviewed. Cardiotoxic AEs were recorded, namely, QT interval prolongation, decrease in left ventricular ejection fraction (LVEF), imbalances in blood pressure (hypertension and hypotension), alterations in heart rate (tachycardia and bradycardia), and thrombosis. Any available dose adjustment recommendations in case of an occurrence of these adverse events were collected. Results: In all, 93 different OAAs had been approved by the EMA and were reviewed. Among them, 51.6% have recognized cardiotoxic AEs and 10.8% can cause alterations in lipid metabolism. A total of 27 (29.0%) OAAs had specific recommendations regarding QT prolongation; 88.9% were listed in the SPC and 59.3% in Lexicomp®. Eight OAAs (9.68%) have reported a decrease in LVEF, and four of these drugs, namely, encorafenib, lorlatinib, ripretinib, and sunitinib, have specific management recommendations. Almost half (49.5%) of currently approved OAAs can potentially alter blood pressure; 34 (36.6%) of them have been reported to cause hypertension and 12 (12.9%) are related to hypotension. Tachycardia and/or bradycardia are associated with 22.6% and 8.6% of the evaluated drugs, respectively. Regarding thrombosis, 30 (32.3%) of the drugs analyzed included the appearance of a thrombus as a possible AE. Conclusions: More than half of the OAAs can produce cardiotoxic effects, with the most frequent being blood pressure alteration and QT interval prolongation with a non-depreciable incidence of LV dysfunction or thrombosis. Before starting the treatment, it is necessary to stratify baseline cardiovascular risk, plan a surveillance schedule, and consider referral to cardio-oncology units.

Achieving excellence in the pharmaceutical care of the surgical patient. / Hacia la excelencia en la atención farmacéutica al paciente quirúrgico.

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the surgical environment has remained one of the areas in which there is less experience. Clinical pharmacist should be integrated into the multidisciplinary care teams so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors throughout the perioperative process. The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care.

[Translated article] Achieving excellence in the pharmaceutical care of the surgical patient.

The perioperative setting is one of the hospital areas with the highest prevalence of medication errors. Despite the wide experience of hospital pharmacists in developing medication safety programs and improvement initiatives, the perioperative setting has remained one of the areas in which there is less experience. Clinical pharmacist should be integrated into the multidisciplinary care team so that they can be involved in the different surgical phases of care, which include from the preoperative assessment to inpatient stay, and finally discharge from hospital. Their work will consist of coordinating and implementing strategies that have been demonstrated to reduce medication errors during the perioperative process. The aim of this paper is to introduce a specialized pharmaceutical care program to achieve excellence in the pharmaceutical care of surgical patients. This program is especially aimed at promoting the figure of the clinical pharmacist in the perioperative setting to guarantee the highest quality and safety in pharmacotherapeutic care throughout all the surgical phases of care.

DPYD Exome, mRNA Expression and Uracil Levels in Early Severe Toxicity to Fluoropyrimidines: An Extreme Phenotype Approach.

Dihydropyrimidine dehydrogenase deficiency is a major cause of severe fluoropyrimidine-induced toxicity and could lead to interruption of chemotherapy or life-threatening adverse reactions. This study aimed to characterize the DPYD exon sequence, mRNA expression and in vivo DPD activity by plasma uracil concentration. It was carried out in two groups of patients with extreme phenotypes (toxicity versus control) newly treated with a fluoropyrimidine, during the first three cycles of treatment. A novel nonsense gene variant (c.2197insA) was most likely responsible for fluoropyrimidine-induced toxicity in one patient, while neither DPYD mRNA expression nor plasma uracil concentration was globally associated with early toxicity. Our present work may help improve pharmacogenetic testing to avoid severe and undesirable adverse reactions to fluoropyrimidine treatment and it also supports the idea of looking beyond DPYD.

Genetic Predictors of Long-term Response to Antitumor Necrosis Factor Agents in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: Inflammatory bowel disease (IBD) is more complex in children and they will have to live with the disease for much longer. For this reason, it is necessary to optimize treatment. The polymorphisms associated with the response to anti-tumor necrosis factor (TNF) drugs in adults with IBD have not been analyzed in children. The aim of the study was to identify genetic variants associated with the long-term response to anti-TNF drugs in children with IBD. METHODS: An observational, longitudinal, ambispective cohort's study was conducted. We recruited 209 anti-TNF-treated children diagnosed with IBD and genotyped 21 polymorphisms previously studied in adults with Crohn disease (CD) using real-time PCR. The association between single-nucleotide polymorphisms (SNPs) and time-to-failure was analyzed using the log-rank test. RESULTS: After multivariate analysis, 3 SNPs in IL10, IL17A and IL6 were significantly associated with response to anti-TNF treatment among patients diagnosed with CD (rs1800872-HR, 4.749 (95% confidence interval [CI] 1.156-19.517), P value < 0.05; rs2275913-HR, 0.320 [95% CI 0.111-0.920], P value  < 0.05; and rs10499563-HR, 0.210 [95% CI 0.047-0.947], P value 0.05, respectively). None of these SNPs were associated with response to infliximab in adults diagnosed with CD. Among patients diagnosed with ulcerative colitis (UC), 1 SNP in LY96 was significantly associated with response to anti-TNF treatment (rs-11465996-HR, 10.220 [95% CI 1.849-56.504] P value < 0.05). CONCLUSIONS: Genotyping of these DNA variants before starting treatment may help to identify children who are long-term responders to anti-TNF drugs, and thus tailor treatment of pediatric IBD.

New DPYD variants causing DPD deficiency in patients treated with fluoropyrimidine.

PURPOSE: Several clinical guidelines recommend genetic screening of DPYD, including coverage of the variants c.1905 + 1G>A(DPYD*2A), c.1679T>G(DPYD*13), c.2846A>T, and c.1129-5923C>G, before initiating treatment with fluoropyrimidines. However, this screening is often inadequate at predicting the occurrence of severe fluoropyrimidine-induced toxicity in patients. METHODS: Using a complementary approach combining whole DPYD exome sequencing and in silico and structural analysis, as well as phenotyping of DPD by measuring uracilemia (U), dihydrouracilemia (UH2), and the UH2/U ratio in plasma, we were able to characterize and interpret DPYD variants in 28 patients with severe fluoropyrimidine-induced toxicity after negative screening. RESULTS: Twenty-five out of 28 patients (90%) had at least 1 variant in the DPYD coding sequence, and 42% of the variants (6/14) were classified as potentially deleterious by at least 2 of the following algorithms: SIFT, Poly-Phen-2, and DPYD varifier. We identified two very rare deleterious mutations, namely, c.2087G>A (p.R696H) and c.2324T>G (p.L775W). We were able to demonstrate partial DPD deficiency, as measured by the UH2/U ratio in a patient carrying the variant p.L775W for the first time. CONCLUSION: Whole exon sequencing of DPYD in patients with suspicion of partial DPD deficiency can help to identify rare or new variants that lead to enzyme inactivation. Combining different techniques can yield abundant information without increasing workload and cost burden, thus making it a useful approach for implementation in patient care.

Improving surgical antibiotic prophylaxis adherence and reducing hospital readmissions: a bundle of interventions including health information technologies.

OBJECTIVES: Infection following orthopaedic surgery is a feared complication and an indicator of the quality of the hospital. Surgical antibiotic prophylaxis (SAP) guidelines are not always properly followed. Our aim was to describe and evaluate the impact of a multidisciplinary intervention on antibiotic prophylaxis adherence to hospital guidelines and 30-day postoperative outcomes. METHODS: The study was carried out from January to May 2016 and consisted of creating a multidisciplinary team, updating institutional guidelines and embedding the recommendations in the computerised physician order entry system which is linked to dose and renal function alerts, educational activities and pharmaceutical bedside care of patients in the orthopaedic department. A prospective pre-post study was carried out in accordance with the Declaration of Helsinki. The following information was recorded: patient and surgery characteristics, adherence to SAP guidelines, surgical site infections, length of hospital stay and rate of readmission 30 days after discharge. Statistical analyses were performed using SPSS 18.0. RESULTS: Eighty three orthopaedic patients of mean±SD age 68.2±17.0 years (44.6% male, 40 in the pre-intervention group and 43 in the intervention group) were included. Cefazolin was the recommended and most commonly administered antibiotic agent. In the intervention group, an improvement in global adherence to guidelines was achieved (76.7% vs 89.9%; p=0.039): antibiotic duration (75.0% vs 97.7%), correct dosage post-surgery (55.0% vs 76.7%), timing of administration (57.5% vs 72.1%), antibiotic pre-surgery prescription (92.5% vs 97.7%). Three surgical site infections were detected in the pre-intervention group and none in the intervention group (p>0.05). Length of hospital stay was reduced by 1 day and readmission decreased by 15% (p=0.038). CONCLUSIONS: SAP is used in daily practice in most orthopaedic patients. The implementation of a multidisciplinary programme based on health technology improved the adherence to guidelines and appeared to reduce the readmission rate.

Evaluating the role of ENOSF1 and TYMS variants as predictors in fluoropyrimidine-related toxicities: An IPD meta-analysis.

To assess the proposed associations of the c.742-227G>A (rs2612091) polymorphism within the Enolase Superfamily Member 1 gene (ENOSF1) and two variants in the adjacent Thymidylate Synthase gene (TYMS): the 5'VNTR 28bp-repeat (rs45445694) and 3'UTR 6bp-indel (rs11280056) with severe toxicity in fluoropyrimidine-treated cancer patients, we performed an individual patient data meta-analysis. Only studies investigating all three-abovementioned variants with fluoropyrimidine-related toxicities were considered for meta-analysis. Associations were tested individually for each study using multivariate regression. Meta-analysis was performed using a random-effects model. One-stage multivariate regressions including tests for independent SNP effects were applied to investigate individual effects of the variants. Multivariate haplotype regression analyses were performed on a pooled dataset to test multi-SNP effects. Of four studies including 2'067 patients, 1'912 were eligible for meta-analysis. All variants were exclusively associated with severe hand-foot-syndrome (HFS) (TYMS 2R: OR = 1.50, p = 0.0002; TYMS 6bp-ins: OR = 1.42 p = 0.0036; ENOSF1 c.742-227G: OR = 1.64 p < 0.0001, per allele). We observed independent effects for ENOSF1 c.742-227G>A and the TYMS 28bp-repeat: each toxicity-associated allele increased the risk for severe HFS (OR = 1.32 per allele, p < 0.0001). Patients homozygous for both variants were at the 3-fold higher risk for severe HFS compared to wild-type patients. Our results confirm an essential role for ENOSF1 c.742-227G and TYMS 2R-alleles in the development of fluoropyrimidine-related HFS. This suggests an important function of these genes in the development of severe HFS. Furthermore, these variants might help stratify patients in studies investigating measures of HFS prevention.

Severe toxicity to capecitabine due to a new variant at a donor splicing site in the dihydropyrimidine dehydrogenase (DPYD) gene.

Severe, life-threatening adverse reactions to capecitabine sometimes occur in the treatment of solid tumors. Screening for dihydropyrimidine dehydrogenase (DPYD) deficiency is encouraged before start of treatment, but the genetic variants that are commonly analyzed often fail to explain toxicities seen in clinical practice. Here we describe the case of a 79-year-old Caucasian female with breast cancer who presented with life-threatening, rapidly increasing toxicity after 1 week of treatment with capecitabine and for whom routine genetic DPYD test resulted negative. DPYD exon sequencing found variant c.2242+1G>T at the donor splicing site of exon 19. This variant is responsible for skipping of exon 19 and subsequent generation of a non-functional DPYD enzyme. This variant has not been described previously but was found in three other members of the patient's family. With this case, we show that exon sequencing of DPYD in patients who experience marked toxicity to fluoropyrimidines and test negative for commonly evaluated variants can prove extremely useful for identifying new genetic variants and better explain adverse reactions causality.

Clinical utility of ABCB1 genotyping for preventing toxicity in treatment with irinotecan.

Preventing severe irinotecan-induced adverse reactions would allow us to offer better treatment and improve patients' quality of life. Transporters, metabolizing enzymes, and genes involved in the folate pathway have been associated with irinotecan-induced toxicity. We analyzed 12 polymorphisms in UGT1A1, ABCB1, ABCG2, ABCC4, ABCC5, and MTHFR in 158 patients with metastatic colorectal cancer treated with irinotecan and studied the association with grade >2 adverse reactions (CTCAE). Among the most frequent ADRs, the SNPs rs1128503, rs2032582, and rs1045642 in ABCB1 and rs1801133 in MTHFR were associated with hematological toxicity and overall toxicity. The SNP rs11568678 in ABCC4 was also associated with overall toxicity. After correction of P values using a false discovery rate, only ABCB1 variants remained statistically significant. Haplotype analysis in ABCB1 showed an 11.3-fold and 4.6-fold increased risk of hematological toxicity (95% CI, 1.459-88.622) and overall toxicity (95% CI, 2.283-9.386), respectively. Consequently, genotyping of the three SNPs in ABCB1 can predict overall toxicity and hematological toxicity with a diagnostic odds ratio of 4.40 and 9.94, respectively. Genotyping of ABCB1 variants can help to prevent severe adverse reactions to irinotecan-based treatments in colorectal cancer.

Drug-to-drug interactions of tyrosine kinase inhibitors in chronic myeloid leukemia patients. Is it a real problem?

With tyrosine kinase inhibitors (TKI), chronic myeloid leukemia (CML) patients are achieving similar rates of survival to the general population and some treatment aspects such as adherence and drug-to-drug interactions (DDI) are becoming increasingly important. Our aim was to investigate the frequency and real clinical consequences of DDI between TKI and concurrent medications in CML. We performed a retrospective multicenter study including 105 patients receiving 134 TKI treatments. Sixty-three patients (60%) had at least one potential DDI. The mean number of concomitant medications was 4.8 (0-19). The mean number of DDI by TKI treatment was 1.2 (0-8); it increased with the number of concomitant medications and age in a significant manner. A total of 159 DDI were detected, involving 55 different drugs. The most common drug classes involved were proton pump inhibitors, statins, and antidepressants. A DDI-related clinical effect (toxicity and/or lack of efficacy) was suspected during the common course of patient follow-up in only five patients (4.7%). This number increased to 20% when data were centrally reviewed. Most of the adverse events (AE) attributed to DDIs were mild. The most common were diarrhea, vomiting, edema, cramps, and transaminitis. Nilotinib and dasatinib showed a tendency towards a higher risk of DDI compared with imatinib. There were no significant differences in AE frequency or in treatment response between patients with or without DDI. Due to their frequency, and their potential to cause clinically relevant effects, DDI are an important aspect of CML management.

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

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. RESULTS: A total of 17 nonsynonymous genetic variants were identified. Of these, five putative damaging SNPs in DPYD, ABCC4 and MTHFR were genotyped in the validation cohort. DPYD rs1801160 was associated with the risk of toxicity (p = 0.029) and MTHFR rs1801133 with delayed administration of chemotherapy due to toxicity (p = 0.047). CONCLUSION: Exome sequencing revealed two specific biomarkers of the risk of toxicity to capecitabine.

Identification of new SNPs associated with severe toxicity to capecitabine.

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. The aim of the present study was to identify new genetic variants by selecting a group of tag SNPs in genes associated with the pharmacodynamics of fluoropyrimidines (CDA, DPYD, ENOSF1, CES1, TYMS, SLC22A7, TYMP, and UMPS). For this purpose, 23 selected SNPs were genotyped on an OpenArray™ platform in a cohort of 301 colorectal cancer patients receiving capecitabine-based chemotherapy. Univariate and multivariate statistical analysis by logistic regression revealed 10 SNPs associated with severe adverse reactions to capecitabine (P<0.05): rs1048977, rs12726436, and rs2072671 in CDA; rs12119882 in DPYD; rs2853741 in TYMS; rs699517 in TYMS/ENOSF1; rs2270860 and rs4149178 in SLC22A7; and rs2279199 and rs4678145 in UMPS. Except for rs2072671, no association had previously been reported between these SNPs and the risk of capecitabine-induced toxicity. The use of tag SNPs to find new polymorphisms related to adverse reactions to capecitabine was successful. These new variants could increase the predictive power of currently available tests and thus prevent severe adverse reactions to capecitabine.

Cost-effectiveness of screening for DPYD polymorphisms to prevent neutropenia in cancer patients treated with fluoropyrimidines.

AIM: To compare the cost of screening for three mutations in the dihydropyrimidine dehydrogenase gene and the costs of treating severe fluoropyrimidine-induced neutropenia. MATERIALS & METHODS: The polymorphisms rs3918290 (DPYD*2A), rs67376798 (DPYD 2846A>T) and rs55886062 (1679T>G, DPYD*13) were genotyped using real-time PCR, TaqMan probes and a rapid cell lysis to provide PCR-ready DNA. RESULTS: We found that genotyping 1000 patients in our center cost €6400 and that the mean cost of treating severe neutropenia was €3044. Therefore, if severe fluoropyrimidine-induced neutropenia is reduced by genotyping the three DPYD variations in at least 2.21 cases per 1000 treated patients, then DPYD genotyping will prove cost effective. CONCLUSION: We demonstrated that real-time DPYD genotyping using TaqMan probes is cost effective in all fluoropyrimidine-based treatments.

Clinical implementation of pharmacogenetics.

In the last decade, pharmacogenetic research has been performed in different fields. However, the application of pharmacogenetic findings to clinical practice has not been as fast as desirable. The current situation of clinical implementation of pharmacogenetics is discussed. This review focuses on the advances of pharmacogenomics to individualize cancer treatments, the relationship between pharmacogenetics and pharmacodynamics in the clinical course of transplant patients receiving a combination of immunosuppressive therapy, the needs and barriers facing pharmacogenetic clinical application, and the situation of pharmacogenetic testing in Spain. It is based on lectures presented by speakers of the Clinical Implementation of Pharmacogenetics Symposium at the VII Conference of the Spanish Pharmacogenetics and Pharmacogenomics Society, held in April 20, 2015.

Variants in CDA and ABCB1 are predictors of capecitabine-related adverse reactions in colorectal cancer.

Adverse reactions to capecitabine-based chemotherapy limit full administration of cytotoxic agents. Likewise, genetic variations associated with capecitabine-related adverse reactions are associated with controversial results and a low predictive value. Thus, more evidence on the role of these variations is needed. We evaluated the association between nine polymorphisms in MTHFR, CDA, TYMS, ABCB1, and ENOSF1 and adverse reactions, dose reductions, treatment delays, and overall toxicity in 239 colorectal cancer patients treated with capecitabine-based regimens. The ABCB1*1 haplotype was associated with a high risk of delay in administration or reduction in the dose of capecitabine, diarrhea, and overall toxicity. CDA rs2072671 A was associated with a high risk of overall toxicity. TYMS rs45445694 was associated with a high risk of delay in administration or reduction in the dose of capecitabine, HFS >1 and HFS >2. Finally, ENOSF1 rs2612091 was associated with HFS >1, but was a poorer predictor than TYMS rs45445694. A score based on ABCB1-CDA polymorphisms efficiently predicts patients at high risk of severe overall toxicity (PPV, 54%; sensitivity, 43%) in colorectal cancer patients treated with regimens containing capecitabine. Polymorphisms in ABCB1, CDA, ENOSF1,and TYMS could help to predict specific and overall severe adverse reactions to capecitabine.