Oxaliplatin plus S-1 with intraperitoneal paclitaxel for the treatment of Chinese advanced gastric cancer with peritoneal metastases

Background In this study, we tried to access the efficacy and safety of oxaliplatin plus S-1 with intraperitoneal paclitaxel (PTX) for the treatment of Chinese advanced gastric cancer with peritoneal metastases. Patients and methods Thirty patients diagnosed with advanced gastric cancer underwent laparoscopic exploration and were enrolled when macroscopic disseminated metastases (P1) were confirmed. PTX was diluted in 1 l of normal saline and IP administered through peritoneal port at an initial dose of 40 mg/m2 over 1 h on day1,8, respectively. Oxaliplatin was administered intravenously at an initial dose of 100 mg/m2 on day1, and S-1 was administered orally at an initial dose of 80 mg/m2 for 14 days followed by 7 days rest, repeated by every 3 weeks. Results Of all these 30 patients, the median number of cycles was 6 (range 2–16) due to the limitation of hematotoxicity and peripheral neuropathy by oxaliplatin. There were 11 (36.7%) patients received conversion surgery. The median progression free survival (PFS) was 6.6 months (95% CI = 4.7–8.5 months) and the median overall survival (OS) was 15.1 months (95% CI = 12.4–17.8 months). The grade 3–4 hematological toxicities were leucopenia (23.3%), neutropenia (23.3%), anemia (16.7%), and thrombocytopenia (20%), respectively. The grade 3–4 non-hematological toxicities were tolerated, most of which were peripheral sensory neuropathy (40%) due to oxaliplatin, diarrhea (20%), nausea and vomiting (26.7%). Conclusions SOX+ip PTX regimen was effective in advanced gastric cancer with peritoneal metastasis. Survival time was significantly prolonged by conversion surgery. Grade 3–4 toxicities were uncommon. Large scale clinical trial is necessary to get more evidence to identify its efficacy. Trail registration ChiCTR, ChiCTR-IIR-16009802. Registered 9 November 2016,

Potential added value of combined DPYD/DPD genotyping and phenotyping to prevent severe toxicity in patients with a DPYD variant and decreased dihydropyrimidine dehydrogenase enzyme activity

Decreased dihydropyrimidine dehydrogenase enzyme activity is associated with severe fluoropyrimidine-associated toxicity. Four clinically relevant variants in the DPYD gene are associated with decreased dihydropyrimidine dehydrogenase activity. However, only ∼25% of DPYD variant carriers show a decreased dihydropyrimidine dehydrogenase activity in peripheral blood mononuclear cells. Objective To investigate if dihydropyrimidine dehydrogenase phenotyping has added value when combined with DPYD genotyping in predicting fluoropyrimidine-related toxicity. Methods Retrospective cohort study in which treatment and toxicity data were collected of 228 patients genotyped for four DPYD variants and phenotyped using an ex vivo peripheral blood mononuclear cell assay. Results Severe toxicity occurred in 25% of patients with a variant and normal dihydropyrimidine dehydrogenase activity, in 21% of patients without a variant and with decreased dihydropyrimidine dehydrogenase activity, and in 29% of patients without a variant and with normal dihydropyrimidine dehydrogenase activity (controls). The majority of patients with a variant or a decreased dihydropyrimidine dehydrogenase activity received an initial dose reduction (68% and 53% vs 19% in controls) and had a lower mean dose intensity (75% and 81% vs 91% in controls). Fifty percent of patients with a variant and decreased enzyme activity experienced severe toxicity, despite the lowest initial dose and whole treatment dose intensity. They also experienced more grade 4/5 toxicities. Conclusions Our results indicate that a combined genotype–phenotype approach could be useful to identify patients at increased risk for fluoropyrimidine-associated toxicity (e.g. patients with a variant and decreased dihydropyrimidine dehydrogenase activity). Because the group sizes are too small to demonstrate statistically significant differences, this warrants further research in a prospective study in a larger cohort.

Abstract 11399: Time to Anti-Arrhythmic for Out-of-Hospital Cardiac Arrest

Introduction: Initial shockable rhythm is the strongest predictor of good outcomes for patients with out-of-hospital cardiac arrest (OHCA). While preclinical models have shown benefit of anti-arrhythmics, clinical trials have shown a very modest impact of anti-arrhythmic drugs, possibly related to real-life delays in drug administration. Little is known regarding the time to administration of anti-arrhythmic drugs or the association of time to drug and outcome. We utilized a national EMS registry to evaluate the time of drug administration and the association with outcomes. Methods: We evaluated the 2018 and 2019 NEMSIS dataset, including all non-traumatic, adult 911 EMS encounters for cardiac arrests with initial shockable rhythm. We then calculated the time from 911 call to administration of anti-arrhythmic. We excluded cases with time to administration less than 0 or greater than 120 minutes. Stratified by initial antiarrhythmic (amiodarone and lidocaine), we created a mixed-effect logistic regression model evaluating the association between every 5 minute increase in time to antiarrhythmic and ROSC. We modeled EMS agency as a random intercept and adjusted the analysis for age, sex, race, bystander witnessed arrest, location of arrest and EMS response time. We excluded EMS witnessed arrests and cases with missing ROSC data. Results: There were 449,630 adult, non-traumatic cardiac arrests identified with 55,142 patients (12.3%) having an initial shockable rhythm; 17,769 (32.2%) received amiodarone and 2,855 (5.2%) received lidocaine initially. The median time in minutes to initial dose of amiodarone was 20.4 with IQR (16-26.7). The median time in minutes to initial dose of lidocaine administration was 20.2 with IQR (15.7-27.0). Increasing time to initial antiarrhythmic was associated with decreased odds of ROSC for both amiodarone (aOR 0.9; 95% CI 0.9-0.94) and lidocaine (aOR 0.9; 95% CI 0.8-0.96). Conclusion: Time to administration of anti-arrhythmic medication varied, but most patients received the first does of anti-arrhythmic drug more than 20 minutes after the initial 911 call. Time to administration of antiarrhythmic was linked to ROSC.

Consensus of experts from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology for the genotyping of DPYD in cancer patients who are candidates for treatment with fluoropyrimidines

Abstract5-Fluorouracil (5-FU) and oral fluoropyrimidines, such as capecitabine, are widely used in the treatment of cancer, especially gastrointestinal tumors and breast cancer, but their administration can produce serious and even lethal toxicity. This toxicity is often related to the partial or complete deficiency of the dihydropyrimidine dehydrogenase (DPD) enzyme, which causes a reduction in clearance and a longer half-life of 5-FU. It is advisable to determine if a DPD deficiency exists before administering these drugs by genotyping DPYD gene polymorphisms. The objective of this consensus of experts, in which representatives from the Spanish Pharmacogenetics and Pharmacogenomics Society and the Spanish Society of Medical Oncology participated, is to establish clear recommendations for the implementation of genotype and/or phenotype testing for DPD deficiency in patients who are candidates to receive fluoropyrimidines. The genotyping of DPYD previous to treatment classifies individuals as normal, intermediate, or poor metabolizers. Normal metabolizers do not require changes in the initial dose, intermediate metabolizers should start treatment with fluoropyrimidines at doses reduced to 50%, and poor metabolizers are contraindicated for fluoropyrimidines.

Optimization of Initial Dose Regimen for Sirolimus in Pediatric Patients With Lymphangioma

Sirolimus is an effective oral treatment for pediatric patients with lymphangioma. The present clinical study in 15 children (0.12–16.39 years of age) examines the effects of underlying factors on sirolimus concentrations through application of a population pharmacokinetic model. Using Monte Carlo simulation, an initial dose regimen for sirolimus in pediatric patients with lymphangioma is presented. It is found that the lower the body weight, the higher the clearance rate and sirolimus clearances are 0.31–0.17 L/h/kg in pediatric patients with lymphangioma whose weights are 5–60 kg, respectively. The doses of sirolimus, 0.07, 0.06, 0.05 mg/kg/day are recommended for weights of 5–10, 10–24.5 and 24.5–60 kg in children with lymphangioma. This study is the first to establish a population pharmacokinetic model for sirolimus and to recommend initial doses in pediatric patients with lymphangioma. Large scale, prospective studies are needed in the future.

Surgical antibiotic prophylaxis administration practices

SETTING: A referral hospital in Kavre, Nepal.OBJECTIVES: To assess 1) compliance with National Antibiotic Treatment Guidelines (NATG), specifically, whether the administration of surgical antibiotic prophylaxis (SAP) (initial dosing and redosing) was in compliance with NATG for patients who were and were not eligible, and 2) development of surgical site infections (SSIs) among patients who underwent surgery in the Department of General Surgery (July–December 2019).DESIGN: This was a retrospective cohort analysis.RESULTS: The analysis included 846 patients, of which 717 (85%) patients were eligible for SAP and 129 (15%) were ineligible. Of those eligible, 708 (99%) received the initial dose; while 65 (50%) of the ineligible did not receive any dose. Of those who received the initial dose, 164 (23%) were eligible for redosing. Of these, only 23 (14%) received at least one redosing and 141 (86%) did not receive it. Overall compliance with NATG was achieved in 75% (632/846) of patients. SSIs occurred in 23 (3%) patients, 8 (35%) of whom did not have SAP administered according to NATG.CONCLUSION: A relatively high overall compliance with NATG for SAP administration was reported. Recommendations were made to improve compliance among those who were ineligible for SAP and those who were eligible for redosing.

Experience of a Strategy Including CYP2C19 Preemptive Genotyping Followed by Therapeutic Drug Monitoring of Voriconazole in Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation

Many factors have been described to contribute to voriconazole (VCZ) interpatient variability in plasma concentrations, especially CYP2C19 genetic variability. In 2014, Hicks et al. presented data describing the correlation between VCZ plasma concentrations and CYP2C19 diplotypes in immunocompromised pediatric patients and utilized pharmacokinetic modeling to extrapolate a more suitable VCZ dose for each CYP2C19 diplotype. In 2017, in our hospital, a clinical protocol was developed for individualization of VCZ in immunocompromised patients based on preemptive genotyping of CYP2C19 and dosing proposed by Hicks et al., Clinical Pharmacogenetics Implementation Consortium (CPIC) clinical guidelines, and routine therapeutic drug monitoring (TDM). We made a retrospective review of a cohort of 28 immunocompromised pediatric patients receiving VCZ according to our protocol. CYP2C19 gene molecular analysis was preemptively performed using PharmArray®. Plasma trough concentrations were measured by immunoassay analysis until target concentrations (1–5.5 μg/ml) were reached. Sixteen patients (57.14%) achieved VCZ trough target concentrations in the first measure after the initial dose based on PGx. This figure is similar to estimations made by Hicks et al. in their simulation (60%). Subdividing by phenotype, our genotyping and TDM-combined strategy allow us to achieve target concentrations during treatment/prophylaxis in 90% of the CYP2C19 Normal Metabolizers (NM)/Intermediate Metabolizers (IM) and 100% of the Rapid Metabolizers (RM) and Ultrarapid Metabolizers (UM) of our cohort. We recommended modifications of the initial dose in 29% (n = 8) of the patients. In RM ≥12 years old, an increase of the initial dose resulted in 50% of these patients achieving target concentrations in the first measure after initial dose adjustment based only on PGx information. Our experience highlights the need to improve VCZ dose predictions in children and the potential of preemptive genotyping and TDM to this aim. We are conducting a multicenter, randomized clinical trial in patients with risk of aspergillosis in order to evaluate the effectiveness and efficiency of VCZ individualization: VORIGENIPHARM (EudraCT: 2019-000376-41).

Initial dose reduction of enzalutamide does not decrease the incidence of adverse events in castration-resistant prostate cancer

Background There was no clear evidence whether the initial dose of enzalutamide affects the incidence of adverse events (AEs), and oncological outcome in patients with castration-resistant prostate cancer (CRPC). Methods The clinical charts of 233 patients with CRPC treated with enzalutamide were reviewed retrospectively. After 1:3 propensity score matching (PSM), 124 patients were divided into a reduced dose group and a standard dose group, and the prostate specific antigen (PSA) response and the incidence of AEs were compared. Results 190 patients with CRPC initiated with standard dose enzalutamide were younger and better performance status compared with 43 patients beginning with reduced dose. After PSM, the baseline characteristics were not different between the standard and the reduced dose group. In the PSM cohort, the PSA response rate was significantly lower in the reduced dose group than in the standard dose group (-66.3% and -87.4%, p = 0.02). The incidence rates of AEs were not statistically different between the groups (22.6% and 34.4%, respectively, p = 0.24). Conclusion Initiating treatment with a reduced dose of enzalutamide did not significantly decrease the incidence rate of AEs, and it showed poorer PSA response rate. There is no clear rationale for treating with a reduced initial dose of enzalutamide to reduce the incidence of AEs.