Hr Infusion Research Articles

Comparison of 24 vs 72-hr octreotide infusion in acute esophageal variceal hemorrhage - A multi-center, randomized clinical trial

BackgroundCurrent guidelines lack clarity about the optimal duration of octreotide therapy for patients with esophageal variceal hemorrhage (EVH). To address this lack of evidence, we conducted a randomized clinical trial (RCT) of 24-hr versus 72-hr continuous infusion of octreotide for patients with EVH. MethodsThis multi-center, prospective RCT (NCT03624517), randomized patients with EVH to 24-hr versus 72-hr infusion of octreotide. Patients were required to undergo esophageal variceal band ligation prior to enrollment. The primary endpoint was rebleeding rate at 72 hr. The study was terminated early due to an inability to recruit during and after the COVID-19 epidemic. ResultsFor patients randomized to 72-hr (n = 19) of octreotide vs 24-hr (n = 15), there were no differences in the need for transfusion, average pRBC units transfused per patient (3 units vs 2 units), infection (5 % vs 0 %), mechanical ventilation (11 % vs 7 %), or the need for vasopressors (5 % vs 3 %), respectively (none of these differences were statistically significantly different). There were 2 re-bleeding events in the 72-hr group (11 %), and no re-bleeding events in the 24-hr group (p = 0.49). 8/15 of patients receiving 24 hr of octreotide were discharged at or before hospital day 3 while none in the 72-hr group was discharged before day 3 (p < 0.001). There was one death (in the 72-hr group) within 30 days. ConclusionsA 24-hr infusion is non-inferior to a 72-hr infusion of octreotide for prevention of re-bleeding in patients with EVH. We propose that shortened octreotide duration may help reduce hospital stay and related costs in these patients.

Pharmacodynamics of taniborbactam in combination with cefepime studied in an in vitro model of infection

ObjectivesTo define the in vitro pharmacodynamics of taniborbactam against Enterobacterales with CTXM-15, KPC, AmpC, and OXA-48 β-lactamases. MethodsAn in vitro pharmacokinetic model was used to simulate serum concentrations associated with cefepime 2G by 1 h infusion 8 h. Taniborbactam was given in exposure ranging and fractionation simulations. Reduction in viable count at 24 h (Δ 24) was the primary end point and four strains were used: Escherichia coli expressing CTXM-15 or AmpC and Klebsiella pneumoniae expressing KPC or OXA-48 enzymes. ResultsTaniborbactam was administered as continuous infusions; ≥4 log kill was attained with taniborbactam concentrations of ≥0.01 mg/L against CTXM-15 E. coli, ≥0.5 mg/L against KPC- and OXA-48 K. pneumoniae, and ≥4 mg/L against AmpC E. coli. Analyses were conducted to determine the pharmacokinetic/dynamic driver for each strain. For E. coli (CTXM-15) and E. coli (AmpC), area under the concentration-time curve (AUC) was best related to change in viable count (R20.74 and 0.72, respectively). For K. pneumoniae (KPC) AUC and T > 0.25 mg/L were equally related to bacterial clearance (R20.72 for both), and for K. pneumoniae (OXA-48) T > 0.25 mg/L was the best predictor (R20.94). The taniborbactam AUC range to produce a 1-log10 reduction in viable count was 4.4–11.2 mg·h/L. Analysis of data from all strains indicated T > MIC divided by 4 was best related to change in viable count; however, curve fit was poor R2 < 0.49. ConclusionsTaniborbactam was effective in combination with cefepime in producing bacterial clearance for B lactam resistant Enterobacterales. The primary pharmacodynamic driver was AUC or time > threshold, both being closely related to antibacterial effect.

#4577 RENAL SAFETY OF FLOT REGIMEN FOR GASTROESOPHAGEAL CANCER

Abstract Background and Aims Currently, peri-operative docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) chemotherapy is the gold standard treatment for patients with locally advanced gastric cancer (LAGC), who undergo peri-operative chemotherapy and surgery. The known nephrotoxicity of both docetaxel and oxaliplatin compounds may limit the its application in CKD population. Nevertheless, limited evidence is available regarding the effects of FLOT regimen on renal function. In our analysis we evaluated the renal safety of FLOT regimen in LAGC population. Method Retrospective data on patient with resectable gastric cancer in four tertiary referral hospital between jan/2018 to jan/2022 have been analyzed. Patient have been treated with docetaxel (60 mg/m2), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), and 5-fluorouracil (2,600 mg/m2 as a 24 hr infusion), all given on day 1 and administered every 2 weeks in 4 administrations before surgery. Serum creatinine, hemoglobin, lymphocytes and CKD-EPI eGFR were detected at baseline and before each cycle. AKI and CKD onset/prevalence were determined according to K-DIGO criteria. Results A consecutive cohort of 90 patients was enrolled. At baseline CKD was present in 16 pts (21.9%). Median eGFR was 84,9 ml/min. In terms of eGFR decay and CKD onset during the treatment cycle, the result of ANOVA indicated no significant differences or relationship with FLOT; Wilks’ Lambda = 0.94, p = 0.354 (Table 1 and Figure 1). AKI incidence was very low with one episode of stage 2 AKI (0,7%) between the 2nd and the 4th treatment cycle. New onset anemia between the 1st and the 2nd cycle was the only significant adverse event observed (p = 0.003). Conclusion According to our results, the pre-operative FLOT regimen seems to have a negligible impact on renal function with very low rate of renal toxicity suggesting the possibility to extend its use even in patient with advanced CKD.

Effect of overexpression of ERK1/2 and MDR1 on chemoresistance in advanced gastric cancer patients.

e16051 Background: Gastric cancer (GC) is late diagnosed disease with a poor prognosis. The emergence of multidrug resistance (MDR) increases the disease burden, and treatment failure in the patients. Several molecular and circulating biomarkers have been identified and evaluated for the clinical relevance in the management of gastric cancer. The aim of this study is to decipher the involvement of ERK1/2 and MDR1 in relation to MDR phenotype and major clinicopathological characteristics in gastric cancer patients. This will help to select effective drug combinations to improve the treatment success rate. Methods: This study recruited 64 individuals with newly diagnosed gastric cancer between 2019 and 2022. Patients were recommended for surgery or neoadjuvant chemotherapy (NACT). NACT group treated with docetaxel (60 mg/m2), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), and 5-fluorouracil (2,600 mg/m2 as a 24 hr infusion), all given on day 1 and administered every 2 weeks before surgery. Based on CECT report, patients were categorized as responders (CRs), partial responders (PRs), and non-responders (NRs). Tissue and blood samples were analyzed for ERK1/2 and MDR1expression using IHC, immuno-blotting and qRT-PCR analyses. Rhodamine123 (Rh123) accumulation assay and flowcytometry was performed to measure the degree of resistance among patients. Descriptive statistics, and Pearson’s Chi-square test was carried out to evaluate the expression distribution of ERK1/2 and MDR1. Results: Out of 64 patients, between the ages of 41-60 (53.08±10.51), 54.5% have ≥5 cm tumor size in the antrum site (56.1%) and diagnosed with stage III (56.1%). Majority of observations were intestinal type (60.6%) with lymphovascular invasion (71.2%). Among all 29.4%, 20.6% and 50.0% were CRs, PRs, &amp; NRs respectively and 36.5% patients underwent NACT. The IHC scoring analysis revealed 25 (37.9%) &amp; 18 (28.6%) individuals for ERK1/2 and 18 (27.3%) and 26 (39.4%) individuals for MDR1 had moderate to strong expressions respectively. Simultaneously, the expressions were highly significant with tumor site (antrum), tumor size (≥5 cm), wall thickening (radiological finding), signet ring cell carcinoma, grade 3, stage III (T3N2), NRs, lymphovascular, peritoneal and serosal invasions (p=0.000). ERK1/2 was more prevalent in diffuse type patients (p=0.000). Also, protein and mRNA level for both genes were more pronounced in NACT group (p&lt;0.005). Flowcytometry showed FLOT receivers had lower Rh123 accumulation, indicating MDR1overexpression (11.5± 8.9) compared to baseline (49.5 ±38.3). The Pearson χ2 test revealed positive correlation between ERK1/2 and MDR1 (p=0.000). Conclusions: ERK1/2 and MDR1 found to over-express in stage III, predicts the degree of resistance and MDR phenotype in the GC patients.

Controlled Hypotension for Functional Endoscopic Sinus Surgery With Two Different Doses of Fentanyl.

Background and Objectives Functional endoscopic sinus surgery (FESS) is a type of minimally invasive surgery done for acute and chronic sinus diseases or paranasal illnesses. The idea of FESS is to preserve the normal anatomy, which is non-obstructing and mucous membranewhile removing tissue obstructing OMC (osteo metal complex) and facilitating drainage. The critical structures, including the brain, orbit, and carotid veins, the lack of adequate operating room, and bleeding that obscures endoscopic vision throughout the procedure may increase the likelihood of unfavorable surgical results.This study seeks to examine the hemodynamic effects of intubation and extubation as well as the impact of fentanyl infusion on lowering blood pressure during FESS procedures. Materials and Methods Sixty-eight patients from the American Society of Anesthesiologistsclasses 1 and 2 who were planned for functional endoscopic sinus operations were randomly split into two groups for this randomized prospective trial. Group 1 patient belonging to the fentanyl 2 mcg per kg bolus 30 minutes before induction followed by 2 mcg per kg per hr infusion for 90 minutes of surgery, and Group 2 patient belonging to fentanyl 1 mcg per kg bolus 30 minutes before induction followed by 1 mcg per kg per hr infusion for 90 minutes of surgery. The significance of the difference in quantitative measures was measured using the student-t test, and the Chi-square test was used to measure upthe difference in proportion. Statistically significant was set at P<0.05. Results Mean systolic blood pressure was higher in members of Group 2 than in Group 1. In contrast to Group 2, Group 1 had considerably better surgical field conditions, surgeon satisfaction on the AONO'S scale, post-operative nausea and vomiting, and a post-operative VAS Score during the first 24 hours. Conclusion Pre-induction Fentanyl with infusion can effectively control hypotension during functional endoscopic sinus surgery.

1733. Stability of Imipenem/Cilastatin/Relebactam under Different Temperature and Administration Conditions

Abstract Background Imipenem/Cilastatin/Relebactam is an FDA-approved combination antibiotic indicated for resistant infections. There is a practical need to extend the shelf life of parenterals given to patients with such life-threatening infections in the hospital setting. The reconstituted drug's shelf life can be extended by storing at subzero temperatures to slow the degradation kinetics. Package insert indicate stability is 2 hrs at room temperature and refrigeration up to 24 hr. The study aims to determine the stability of the combination in polyvinyl chloride (PVC) infusion (IV) bags when stored at room temperature, refrigerated in addition to continuous infusion CADD pumps. Methods Drug vials (Merck &amp; Co) were reconstituted to 5mg/mL (imipenem) in a 100mL normal saline. To avoid further degradation, samples were collected and mixed 1:1 with stabilizing buffer, then frozen at -80 °C within 5 minutes. For room temperature stability, 6 bags were prepared and stored at (24°C). 0.5ml samples were collected at 0, 2, 4, 6, 8, 12, 24 h from each bag at each time point. For refrigeration stability, 6 bags were prepared and refrigerated at 4 °C. At each time point (24, 36, 48, 60, 72, 84, 96,108, 120h), a sample of 0.5-mL is taken from each bag and frozen at −80 °C. For continuous ambulatory drug delivery (CADD) infusion devices stability, the reconstituted drug is loaded to 2g/200 mL cassettes (for 24-hr infusion) continuous infusion and 1g/100mL (for 12-hr infusion). The cassettes are immediately attached to the infusion pump and placed in a cold pouch with gel packs. After the initial 0.5 mL, 0-h samples from each pump, the pumps are sampled at 4, 8,12, 16, 20, and 24 hours for 2g/ 200mL cassettes and 2, 4, 8, 12 h for 1g/100 mL. Cut off for stability was set at 90% of the original concentration. Chemical assay was performed by a validated HPLC method. Results See tables Table 1:CADD pumps, concentrations are in mg/mL. Imi; imipenem, Rel; relebactam, Cil; Cilastatin, CADD; continuous ambulatory delivery device, SD; standard deviationTable 2:PCV bags, concentrations are in mg/mL. Imi; imipenem, Rel; relebactam, Cil; Cilastatin, PVC; polyvinyl chloride, SD; standard deviation Conclusion Imipenem/relebactam/cilastatin drug product was stable for 12 hrs in CADD pumps 100mL, 16 hrs in 200 mL, 108 hours in refrigerated PVC bags and 12 hrs at room temperature. The extended stability data will assistant pharmacy departments in optimizing drug preparation and storage, nursing time and minimize drug waste improving overall cost and efficiency of drug administration. Disclosures Islam Ghazi, PharmD, Merck And Co Inc: Grant/Research Support David Nicolau, PharmD, Marck and Co Inc: Advisor/Consultant|Marck and Co Inc: Grant/Research Support.

Science, Medicine, and the Anesthesiologist

Science, Medicine, and the Anesthesiologist

The Evaluation of Meropenem Dosing Regimens Against ESBL-Producing Escherichia coli in ICU Patients Using Monte Carlo Simulation.

PurposeTo evaluate the optimal dosing regimens of meropenem against extended-spectrum beta-lactamase-producing Escherichia coli (ESBL E. coli) in critically ill patients with varying degrees of renal function using Monte Carlo simulation (MCS).MethodsThe MCS was performed using the minimum inhibitory concentration (MIC) data from Right Laboratory and Health Screen in Naypyitaw, Myanmar, as well as reported meropenem pharmacokinetic parameters in the target population and the pharmacokinetic-pharmacodynamic index. For each dosing regimen, 10,000 virtual patients were generated to assess the probability of target attainment (PTA) and the cumulative fraction of response (CFR). The most effective dosage regimens were determined using PTA and a CFR of 90%.ResultsESBL E. coli made up 93 of the 396 clinical E. coli isolates, and they are all multidrug-resistant, with resistance to at least five antibiotic classes. The MIC50 and MIC90 were determined to be 0.25 μg/mL. The PTA was affected by five factors: creatinine clearance (CLcr), vasopressor usage, MIC, infusion time, and dosage fractionation. In patients who did not receive vasopressors, the current regimens (US-FDA and EMA) were ineffective in all renal function for MIC >0.25μg/mL. In the subset group of CLcr >80 mL/min for MIC 2μg/mL, the maximum total daily dose of 6g/day (2g q 8hr; 3hr infusion) was still ineffective, but 4g/day (1g q 6hr; 3hr infusion) achieved 98.96% PTA. Almost majority of the simulated regimens produced >90% PTA in vasopressor-dependent patients with all levels of renal function, resulting in a decreased total daily dose requirement.ConclusionFor high MIC (>1μg/mL) patients who do not use vasopressors and have a CLcr >80 mL/min, a combination of dosage fractionation and the extended infusion was considered as an effective technique to maximize target attainment. Neither prolonged infusion nor dosage fractionation should be explored in patients using vasopressors.

Blood tests to predict one- to two-year survival of patients with difficult cancers.

e16158 Background: A sequence of drug combinations produces &gt; 1 median (M) -strong 2-year (yr) survival (S) (Bruckner et al AACR 14 Antica Res (ACR) 16, 18 SIGO 19). Trials included high-risk patients (pts). Each initial series has 5-yr Ss, after pts were referred for hospice care. Prognostic ALAN blood tests (Ts) have been validated for stage IV (Adv) Cholangiocarcinoma (CCA) (Salati et al EuJCa18). Other Ts predict unexpected favorable (F) S of pts with gastric ca, PS 2-3. Bruckner et al JAMA, 82); but, there is little known about Ts for resistant (R) Ca. Methods: Planned Kaplan-Meier intent to treat analysis to find Ts that: expand eligibility (El) for therapy; identify biomarkers that predict therapy can prolong S and identify new hypotheses for therapy. El pts have:R to test drugs, Pancreatic (PC), Intrahepatic bile duct, CCA, Colon, CRC and new (N) APC. All series: -/+ high risk, -/+ aged, PS 0-2. El: Helsinki criteria- consent, recovered from severe (gr3) toxicity; able to reach office, -/+ help, and S &gt; 6 wks. Inel: CNS involved, IV needed, F clinical factors predict 1 yr MST. Ts include A.L.A.N. scores, (AS) (Salati ibid) and other blood Ts (ACR ibid, Lavin et al CTR 82) Therapy GFLIO in mg/M2: gemcitabine 500, leucovorin 180, fluorouracil 1200, 24 hr infusion. Irinotecan 80 D2 Oxaliplatin 40. Then for progression (pg), add docetaxel 20-25, except CRC mitomycin C 4-6; next pg add cetuximab, except APC or KRAS-M, weekly, and next pg replace cetuximab with bevacizumab 10mg/kg ibid ACR 16. Results: At all ages, overall (O) S is &gt; 1 yr for RCRC, and NAPC and sets with any 1 F or UnF T other than &lt; 3.1 Albumin (Alb) or &lt; 2.1 lymph/monocyte ratio (LMR) b For CCA, 17R/16N, OMS &gt; 2 yrs 66% of pts and ≥ 2 yrs for all test sets except UnF, 26% of pts, MS 17 mos, with low Alb. For CRC: 50R OMS is 16.5 mos; 42% S 2 yrs, Fav Ts: MS &gt; ̃ 2yrs, 39-82% of pts have FTs; Neutrophil Lymphocyte Ratio (NLR); &lt; 3.1, 61% S 2 yrs, p &lt; .02; Lymphs &gt; 1.5, 53% S 2 yrs, p &lt; .02; AS 0; 59% S 2 yrs, p &lt; .06; Platelets &lt; 300,000, 54% S 2 yrs, p &lt; .06; Alb: ≥ 3.5, 48% S 2 yrs, p &lt; .11. For N-APC: 53 pts, OS is 14.5 mos and &gt; 12 mos in sets with any 1 UnF T other than Alb or LMR. FTs: MST 16.4-18 mos. 34-77% of pts have FTs; Alb ≥ 3.5, 34% S 2 yrs, p &lt; 0.001; WBC &lt; 10, 29% S 2 yrs, p &lt; .06; AS 0-2, 35% S 2 yrs, p 2.7E-7. For R-PC: 53 pts, OS is 12 mos for 44% of pts, FTs: MST 13.6-17 mos, 21-70% of pts have FTs: Alb ≥ 3.5 30% S 2 yrs, p .0004; AS: 0, 41% S 2 yrs, p .0006; NLR &lt; 3, 37% S 2 yrs, p &lt; .02. GFLIO’s &lt; 5% gr3 induction toxicity, is reversible, with no hospitalization, neutropenic fever or gr3 neuropathy. Conclusions: Robust Ts identify many difficult pts with median &gt; 1 and testable prospective &gt; 2 yr rates of S. Ts warrant development: validation with GFLIO and other therapy and other cancers; to improve Ts, models for eligibility and geriatric criteria; to identify false -/+ trials; and personalize trials to correct UnF Ts. FTs, with GFLIO, can change prognosis and practice for &gt; 50% of pts now advised “against” any therapy due to a clinical estimate of “less than 6 -10 mos to live.” Clinical trial information: NCT01905150.

1858-P: P38 MAPK Inhibition Protects against FFA-Induced Insulin Resistance and Hepatic Fat Accumulation

The liver plays a central role in metabolism. Yet, it is unclear how hepatic metabolic dysregulation promotes insulin resistance and hepatic steatosis. Some studies have investigated the role of hepatic p38, a stress mitogen-activated protein kinase (MAPK), in hepatic fat accumulation and insulin resistance in models of obesity. However, the role of p38 in free fatty acid (FFA) induced hepatic fat accumulation and insulin resistance has not been previously investigated. Moreover, the role that p38 MAPK plays in hepatic glucose and lipid metabolism is still controversial. Here, using both genetic and pharmacological models, we investigated whether the inhibition of p38 MAPK reverses FFA-induced hepatic fat accumulation and insulin resistance. Cannulated Wistar rats were intravenously infused with one of four treatments for 48 hours: Saline (SAL), Intralipid+Heparin (IH), IH+p38 MAPK inhibitor - SB239063 (IH+SB) and SB239063 (SB) alone. After 48hr infusion, the liver was collected and stained with Oil Red O to determine hepatic fat accumulation. IH rats had significantly greater hepatic fat accumulation compared to SAL rats (p&amp;lt;0.05). IH+SB rats were protected from FFA-induced hepatic fat accumulation. To assess the role of p38 on FFA-induced insulin resistance, liver-specific p38 knockout mice and wild type mice were infused with ethyl-oleate and ethyl palmitate (EtOP) or ethanol (control) for 48 hrs. After 46 hours of the infusion, the mice underwent a hyperinsulinemic-euglycemic clamp to determine insulin sensitivity. Results thus far suggest that genetic inhibition of p38 MAPK in the liver protects from FFA-induced insulin resistance in the periphery (p=0.06), consistent with tissue cross-talk also observed by our lab in liver-specific p38 knockout mice using a high fat diet model. In conclusion, our data indicates that both the pharmacological and genetic inhibition of p38 has a protective effect on FFA-induced hepatic fat accumulation and insulin resistance. Disclosure D.Y. Joseph: None. S.L. Rivers: None. A. Giacca: None. Funding Canadian Institutes of Health Research (503010)

Randomized Phase III Study of FOLFOX Alone and with Pegilodecakin as Second-line Therapy in Patients with Metastatic Pancreatic Cancer (SEQUOIA).

637 Background: Effective therapies are limited for advanced metastatic pancreatic ductal adenocarcinoma (PDAC) patients (pts) who have progressed after 1st line gemcitabine-based chemotherapy (Gem). FOLFOX has clinical benefit in Gem-refractory PDAC pts. A phase 1 trial demonstrated promising activity with pegilodecakin (PEG; pegylated IL-10) and FOLFOX in Gem-refractory PDAC pts, providing rationale for the phase 3 trial (SEQUOIA; NCT02923921). Methods: SEQUOIA is a randomized phase 3 study of FOLFOX alone or with PEG in Gem-refractory PDAC pts. Pts were randomized 1:1, excluding pts with prior surgery and radiation, and received FOLFOX ( dI-Leucovorin [400 mg/m2], oxaliplatin [85 mg/m2] followed by bolus 5-FU [400 mg/m2], and a 46-48 hr infusion of 5-FU [2400 mg/m2]) on day 1 of a 14-day cycle up to 12 cycles. PEG + FOLFOX arm received PEG (0.4 mg/d if ≤80kg and 0.8mg/d if &gt; 80 kg) on Days 1-5 then Days 8-12 + FOLFOX. Pts could continue PEG monotherapy (0.8mg/d if ≤ 80 kg and 1.6 mg/d if &gt; 80 kg) after FOLFOX discontinuation. Primary objective was OS. Secondary objectives included PFS, ORR per RECIST 1.1, and safety. Assuming OS HR of 0.74, the study was powered to 85% at 2-sided α = 0.05 with ~566 pts to detect superiority of PEG + FOLFOX. Results: As of Sept 9, 2019, 567 pts were randomized to PEG + FOLFOX (283) or FOLFOX (284). The majority (94.7%) had 1st line Gem+nab paclitaxel. The mOS was similar between FOLFOX + PEG arm [5.8 months] and FOLFOX arm [6.3 months] with HR = 1.045 (95% CI [0.863, 1.265], p = 0.6565). No statistical difference was observed for PFS, mPFS was 2.1 months in both arms with HR = 0.981, (95% CI [0.808, 1.190], p = 0.8144). ORR was 4.6% on the PEG+FOLFOX arm and 5.6% on the FOLFOX arm. Grade ≥3 adverse events that were 5% higher on the PEG+FOLFOX arm included thrombocytopenia (25.2% vs. 3.6%), anemia (16.2% vs. 4.0%), neutropenia (29.5% vs. 22.7%), and fatigue (17.6% vs. 10.8%). Conclusions: The addition of PEG to FOLFOX did not improve efficacy (OS, PFS, ORR) in advanced PDAC pts who have progressed after 1st line Gem-containing therapy. Safety findings were consistent with previous data observed from PEG + chemotherapy; toxicity was manageable and tolerable. Clinical trial information: NCT02923921.

Treosulfan Metabolite (S, S-EBDM) Pharmacokinetics Influences Regimen Related Toxicity in Patients with Beta Thalassaemia Major Undergoing HSCT

A toxicity reduced conditioning regimen containing Treosulfan (Treo), Fludarabine (Flu), Thiotepa in patients with class III high risk thalassemia major (TM) has significantly improved transplant outcomes compared to the historical Busulfan/cyclophosphamide based myeloablative regimen (Mathews et al, 2013). However, complications related to mixed chimerism, rejection and regimen related toxicity remain. Analysis of Treo pharmacokinetics (PK) in TM showed significant inter individual variation but no association with HSCT outcome (Mohanan et al, 2018). This may be attributed to the fact that only the pro-drug Treo was measured and not its active metabolites. Treo, administered as a prodrug, is converted non-enzymatically to its active metabolite monoepoxide 2S, 3S-1,2-epoxybutane-3,4-diol-4-methanesulfonate (S, S-EBDM) and (2S,3S)- 1,2:3,4-diepoxybutane (S, S-DEB) that causes cytotoxicity. We have now assessed the PK of both Treo and S, S-EBDM and the factors which may influence the inter-individual variation in PK, and their impact on HSCT outcome in patients with TM. Fifty-six patients with TM undergoing HSCT between January 2016 and June 2019 with Flu/Treo based conditioning regimen (Flu 40mg/m2/day x 4 days as a 1hr infusion and Treo as 14g/m2/day x 3 days infused at 5g/hr) were included in this analysis. Selected functional polymorphisms in NAD(P)H Quinone Dehydrogenase-1 (NQO1) and Glutathione S-transferase (GST) genes that showed association with Treo PK based on our previous report (Pai et al, Abstract. Proceedings of BMT Tandem Meetings 2018) were screened. Plasma Treo and S, S-EBDM were measured using an LC-MS/MS method. Treo and S, S-EBDM PK were estimated using nonlinear mixed effects modeling via Monolix 5.0.1. The covariates tested were age, sex, body weight, BSA, serum ferritin, NQO1 3'UTR (rs10517) and GSTA1*B polymorphisms. The influence of Treo &amp; S, S-EBDM PK and polymorphisms on graft rejection, regimen related toxicities (RRT), chimerism status, overall and event-free survival were estimated using logistic regression analysis. A two-compartment model best described the PK of Treo and S, S-EBDM. Two and 11-fold inter-individual variation was observed in Treo and S, S-EBDM PK respectively. Among the covariates tested, Treo Cl decreased with age (p=0.03) while, S, S-EBDM apparent Cl increased in patients with NQO1 3'UTR variant (p=0.02) and decreased in patients with GSTA1*B variant genotype (p=0.02). Neither Treo AUC nor clearance showed association with HSCT outcome. However, high S, S-EBDM AUC (213. Vs 130 mg*hr/mL, p=0.016) and low S, S-EBDM apparent Cl (68 Vs 122 L/hr/m2, p=0.013) were significantly associated with increased incidence of sinusoidal obstruction syndrome (SOS). Also, on quartile analysis, patients with S, S-EBDM AUC &gt;210 mg*hr/mL and Treo/S, S-EBDM AUC ratio &gt;18 mg*hr/mL showed increased incidence of SOS (p=0.006 &amp; p=0.026 respectively). Multivariate analysis adjusting for known clinical risk factors also showed in addition to age, only high S, S-EBDM AUC to be significantly associated with increased incidence of SOS (p=0.013). No association between rejection or mixed chimerism and Treo/S, S-EBDM PK was observed, probably due to very low incidence of graft rejection in this cohort (4/56; 7%). Our study suggests that active metabolite S, S-EBDM influences SOS following HSCT in TM patients. It is well acknowledged that Treo to S, S-EBDM conversion is a non-enzymatic nucleophilic substitution reaction and there is a difference in the disposition of Treo and S, S-EBDM in different organs including the liver (Romanski et al, 2017). Treo metabolites exert their cytotoxic activity by both DNA-DNA and DNA-protein crosslinks in these organs. The role of Treo metabolites in exhausting essential cellular proteins like GSH and NQO1 as well as the effect of GST/NQO1 variants in influencing Treo metabolism in liver which may then impact the incidence and severity of SOS need further evaluation. Disclosures No relevant conflicts of interest to declare.

783P - Perioperative chemotherapy with docetaxel, oxaliplatin, fluorouracil and leucovorin (FLOT) versus epirubicin, platinum and capecitabine or flourouracil (EOX/ECF) in resectable gastric or gastroesophageal junction adenocarcinoma: Safety and response data from India

BackgroundGastric and GEJ cancers are one of the top four cancers in India with poor 5-year survival. Post ASCO 2017, we switched to docetaxel-based peri-operative chemotherapy (FLOT) which is the new standard of care. In this audit, we report the pathological response and toxicity of FLOT compared to our older standard (EOX/ECF). MethodsWe analysed our database of 118 patients with gastric or GEJ adenocarcinoma treated at our center from May 2011 to April 2019. 85 patients (72%) received perioperative chemotherapy with three pre-operative and three post-operative 3-week cycles of either EOX (50mg/m2 Epirubicin and 130mg/m2 Oxaliplatin on Day 1 plus 1250mg/m2 Capecitabine for 21 days) or ECF (50mg/m2 Epirubicin and 60mg/m2 Cisplatin on Day 1 plus 800mg/m2/day Fluorouracil as continuous intravenous infusion for 5 days). 33 patients (28%) received four pre-operative and four post-operative 2-week cycles of intravenous FLOT (50mg/m2 Docetaxel, 85mg/m2 Oxaliplatin, 200mg/m2 Leucovorin and 2600mg/m2 Fluorouracil as 24hr infusion on Day 1). We compared the toxicity, and pathological tumor response rates of patients on EOX/ECF and FLOT regimens. ResultsThe patients were aged 30 to 73 years (Median 58 years) and 40 (34%) were women. 85 patients received either EOX/ECF and 33 received FLOT chemotherapy. 64 (75%) patients in EOX/ECF underwent gastrectomy among whom eight (12.5%) had pathological Tumour Regression Score (TRS) of 0 or 1. 24 (72%) patients in FLOT group have undergone gastrectomy of whom six (25%) had TRS of 0 or 1. 34 (40%) patients completed full EOX/ECF regimen while 20 (60%) completed full FLOT. The commonest reason for not completing the peri-operative chemotherapy was toxicity in EOX/ECF group (29%) and refusal to undergo surgery (21%) in the FLOT group. 15% patients did not complete FLOT chemotherapy due to toxicity. ConclusionsFLOT regimen is a better tolerated perioperative therapy in Indian patients achieving higher pathological response compared to EOX/ECF regimen. The patients in both groups are currently on follow up to capture the relapse free survival duration. Legal entity responsible for the studyTanuj Chawla. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) as preoperative and postoperative chemotherapy compared with surgery followed by chemotherapy for patients with locally advanced gastric cancer: a propensity score-based analysis.

Introduction: Docetaxel, oxaliplatin, leucovorin, and 5-fluorouracil (FLOT) may improve overall survival (OS) in patients with locally advanced gastric cancer (LAGC); however, evidence for its use as a standard treatment has not been established in China. The aim of this study was to investigate the effectiveness, safety, and feasibility of the FLOT regimen as neoadjuvant chemotherapy in Chinese patients with resectable LAGC.Methods: We conducted an observational study to compare the effectiveness of FLOT regimen consisting of docetaxel (60 mg/m2), oxaliplatin (85 mg/m2), leucovorin (200 mg/m2), and 5-fluorouracil (2,600 mg/m2 as a 24 hr infusion), all given on day 1 and administered every 2 weeks versus initial surgery followed by chemotherapy in patients with clinical T3–4 LAGC. OS was compared by using the Cox proportional hazards regression model and the Kaplan–Meier curve adjusted by inverse probability of treatment weighting (IPTW) and propensity score-matched (PSM) analysis. In addition, we performed subgroup analyses to determine the effectiveness of the FLOT regimen in clinically relevant patient subsets.Results: Overall, 47 patients who received initial FLOT chemotherapy and 269 patients who received initial surgery were enrolled in this study. In the PSM analysis, the FLOT-first group showed favorable OS compared with the surgery-first group (41 vs 41 [HR, 0.416; 95% CI, 0.218–0.794; P=0.008]), and 3-year survival rates were 58.7% and 30.9% in the FLOT-first group and surgery-first group, respectively. IPTW analysis showed similar results. However, the effect of FLOT was low (HR, 0.868; 95 CI%, 0.215–3.504) in patients without lymph node metastasis.Conclusion: Our study suggests that preoperative FLOT chemotherapy is safe and feasible. In terms of OS, FLOT may be superior to initial surgery followed by chemotherapy in reducing morbidity with resectable LAGC.

A randomized phase II study comparing oral S-1 plus 24-hour infusion of irinotecan (Iri) and bevacizumab (Bev) with FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer (MCRC).

613 Background: FOLFOX or FOLFIRI plus Bev is a first-line treatment for MCRC. Recent studies have confirmed that oral S-1 combined with Iri and Bev is equivalent to FOLFIRI plus Bev. Iri is usually administered as a short-term 90-min. infusion. However, the cytocidal activity is S-phase specific, and carboxylesterases, that convert Iri into SN-38, are less likely to become saturated when Iri is given as a long-term infusion. Therefore, a low dose of Iri given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare this regimen with FOLFIRI plus Bev. Methods: The subjects comprised 120 chemotherapy-naïve patients with MCRC. The study group received 24-hr infusion of Iri at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1 to 14. The FOLFIRI group received Iri at a dose of 150 mg/m2, 5-FU given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2400 mg/m2 as a 46 hr-infusion, 200 mg/m2 of leucovorin on days 1 and 15. Bev was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was the 1 y progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). Results: From October 2013 through December 2017, a total of 61 patients assigned to receive IRIS plus Bev (the A group) and 59 patients assigned to receive FOLFIRI plus Bev (the B group) were included in the analysis. The 1y RFS was 37.3% in the A group and 17.0% in the B group (p = 0.0281). The PFS was 10.2 mon in the A group and 10.0 mon in the B group, and the median OS was 27.0 mon and 28.6 mon, respectively (p = 0.26, p = 0.68). RR was significantly higher in the A group (87.0%) than in the B group (61.7%) (p = 0.005). The main grade 3 or 4 AEs were neutropenia (27.8%) and diarrhea (11.1%) in the A group and neutropenia (23.4%) and leukopenia (6.4%) in the B group. Conclusions: Our results showed that Iri, given biweekly as a 24-hour infusion in combination with oral S-1 and Bev, is a highly effective and well-tolerated regimen for the first-line treatment of MCRC. Clinical trial information: UMIN000014664.

Modeling gold nanoparticle biodistribution after arterial infusion into perfused tissue: effects of surface coating, size and protein corona

A detailed understanding of the factors governing nanomaterial biodistribution is needed to rationally design safe nanomedicines. This research details the pharmacokinetics of gold nanoparticle (AuNP) biodistribution after arterial infusion of 40 or 80 nm AuNP (1 μg/ml) into the isolated perfused porcine skin flap (IPPSF). AuNP had surface coatings consisting of neutral polyethylene glycol (PEG), anionic lipoic acid (LA), or cationic branched polyethylenimine (BPEI). Effect of a porcine plasma corona (PPC) on 40 nm BPEI and PEG-AuNP were assessed in the IPPSF. Au concentrations were determined by ICP/MS and arterial to venous concentration-time profiles were analyzed over 8 hr (4 hr infusion, 4 hr washout) using a two-compartment pharmacokinetic model. IPPSF viability and vascular function were assessed by change in glucose utilization, vascular resistance, or weight gain after perfusion. All AuNP demonstrated some degree of AuNP arterial extraction and skin flap retention, as well as enhanced kinetic parameters of tissue uptake; with BPEI-AuNP consistently having the greatest biodistribution even with a PPC. Toxicological effects were not detected. Transmission electron microscopy confirmed intracellular uptake of AuNP. These studies paralleled previous in vitro cell culture studies using the same AuNP in human endothelial and renal proximal tubule cells, hepatocytes, keratinocytes, showing BPEI-AuNP having the greatest uptake, although the presence of a PPC did not reduce IPPSF biodistribution as in the cell culture studies. These findings clearly indicate arterial to the venous extraction of AuNP after infusion with the magnitude of extraction being greatest with the BPEI surface coating and provide data and model structure necessary to construct the whole body physiologically based pharmacokinetic models capable of utilizing available in vitro data.

Improved Outcome and Decreased Morbidity and Mortality Rates of B-Cell Malignancies with Less Intensive Chemotherapy Induction: Experience in a Single Institution

Background: High-Dose chemotherapy is necessary one of the most important tools for improving response rates and for decreasing relapse rate in childhood B-cell malignancies. However, deaths during induction or in Complete Remission (CR) in children with higher disease burden had adversely influenced pEFS in our setting, and for this reason an accomplished clinical support is mandatory for achieving these better results.Objective: Our aim was to diminish morbidity and mortality of patients with B-cell malignancies with the administration of a reduced intensity BFM-based induction phase, plus the addition of rituximab in a pilot study. We also retrospectively analyzed the outcome of this group of patients.Methods: This is a prospective study, single arm, non-randomized local trial for treatment of B-cell malignancies. Between December-2008 and March-2016, 81 pts consecutive (<16 years/old) (52:M/29:F) were enrolled in a protocol HPG-09, and 70 of them resulted evaluable.Patients were stratified according stage and DHL level in Risk-1, Risk-2, Risk-3 and Risk-4. Risk-4 included patients with stage IV and stage III with DHL levels higher than 1,000 U/dl.The pathology, flow-cytometry and cytogenetic findings disclosed 60 cases of Burkitt Lymphoma, 11 diffuse large B cell Lymphomas, 9 mature-B acute lymphoblastic leukemia, and 1 Precursor-B ALL with with t(8;14).The treatment locally-none BFM-counterpart included 4 doses of Rituximab administered to Risk-4 cases during early phases of treatment and intensified chemotherapy with HDMTX (24 hr) 5 g/m2, plus reduced intensity induction with pre-phase followed by A1 block (MTX 1 g/m2 4 hr infusion), in order to decrease morbidity and early mortality rates.Results: Distribution of patient according to risk-groups was: Risk-1 (n=2) 2%, Risk-2 (n=9) 11%, Risk-3: (n=13) 16% and Risk-4 (n=46) 57% of cases. Median DHL= 3,642 (range: 396-33,673) UI/dl, CNS+ cases was observed in 6 cases. Complete remission (CR) was achieved in 95.1% of the cases and 4.9% of patients died in early phases of treatment. From patient who achieve CR, 6 adverse events were observed (all of them in Risk-4 group): 2 relapses and 4 death in CR (1 Steven´s-Johnson Syndrome, 2 tumor lysis syndrome plus CID and 1 patient died after extensive initial surgery) The pEFS for R1, R2, and R3 was 100%. With a median follow-up of 48 (range:6-61) months, the pEFS (SE) for all risks groups was 91 (4)% and for Risk-4 85 (6)%.Conclusions: Risk-4 group accounted for 66% of the total population of patients, defining a more aggressive disease prevalence in our setting. Locally-adapted strategy based on BFM experience was successfully implemented, reducing induction intensity and with the incorporation of 4 doses of Rituximab. The outcome of this group of patients was very good. Reduction of induction intensity and addition of Rituximab resulted in low mortality rate and excellent survival outcome. DisclosuresNo relevant conflicts of interest to declare.

PROLONGED INFUSIONS OF KETAMINE AND IMPACT ON INFECTIONS AND WASTE

AimKetamine is used for post-operative analgesia. There has been recent disruption in it's supply. It is usually prescribed by patient's weight (3 mg/kg in 50 ml 0.9% saline) at a...

Effect of intravenous lidocaine on the transcerebral inflammatory response during cardiac surgery: a randomized-controlled trial.

Postoperative cognitive dysfunction (POCD) occurs frequently after cardiac surgery. The pathophysiology of POCD remains elusive, but previous work showed that intravenous lidocaine may be protective against POCD, possibly by modulating cerebral inflammation. We hypothesized that intravenous lidocaine would attenuate the cerebral inflammatory response to cardiopulmonary bypass (CPB) by reducing the transcerebral activation gradients of platelets, leukocytes, and/or platelet-leukocyte conjugates. We studied 202 patients undergoing cardiac surgery with CPB in this prospective randomized double-blinded placebo-controlled trial. Subjects were randomized to receive either intravenous lidocaine (bolus + 48-hr infusion) or placebo (identical infusion volume and duration). Paired jugular venous and radial arterial blood samples were drawn at several time points and analyzed by fluorescence-activated cell sorting to identify activated platelets and platelet-leukocyte conjugates. Transcerebral activation gradients were calculated by subtracting arterial values from venous values and were compared between groups using repeated measures regression models with covariate adjustment for age, sex, surgery type, and CPB duration. Beginning after aortic cross-clamp release and peaking ten minutes after the termination of CPB, the mean (SD) transcerebral activation gradient of platelet-monocyte conjugates decreased in lidocaine-treated vs placebo-treated patients [-1.84 (11.47) mean linear fluorescence intensity (MLFI) vs 1.46 (13.88) MLFI, respectively; mean difference, -4.08 MLFI; 95% confidence interval, -7.86 to -0.29; P = 0.03). No difference was seen at any time point for activated platelets or for platelet-neutrophil conjugates. While lidocaine did not affect the systemic or transcerebral activation of platelets or leukocytes, we did observe a reduction in the transcerebral activation of platelet-monocyte conjugates after aortic cross-clamp release. This may be a manifestation of reduced cerebral inflammation during cardiopulmonary bypass in response to treatment with lidocaine. This trial was registered at ClinicalTrials.gov (NCT00938964).

Abstract 212: Andexanet Alfa, a Universal Antidote for Reversal of Anticoagulation of Factor Xa Inhibitors in Healthy Human Volunteers

Introduction: Andexanet alfa (AnXa) is a recombinant modified fXa molecule that acts as a specific antidote for fXa inhibitors. We report clinical results in healthy subjects anticoagulated with apixaban (apix), rivaroxaban (riva), edoxaban (edox), or enoxaparin (enox), demonstrating rapid and sustained reversal of anticoagulation following administration of AnXa. Methods: These were Phase 2/3 randomized, double-blind, placebo-controlled studies in healthy subjects. In Phase 2, about153 subjects age18 - 45 were given one of the fXa inhibitors (apix 5 mg BID, riva 20 mg QD, edox 60 mg QD or enox 40 mg QD) for 6 days. AnXa or placebo (3:1 randomization) was given IV on Day 6, 3hrs after the last inhibitor dose (∼inhibitor Cmax). Safety was followed through Day 48. A range of AnXa doses (bolus or bolus+infusion) was evaluated by correction of biomarkers (anti-fXa activity, free inhibitor concentrations and thrombin generation (TG)). In Phase 3 (ANNEXA™), older subjects age 50 to 75 were dosed with apix (5 mg BID) or riva (20 mg QD) for 4 days. ANNEXA™-A had 63 subjects treated with apix. AnXa (400 mg bolus; 400 mg bolus plus 4 mg/min x 2hr infusion) or placebo (3:1 randomization) was given on Day 4, 3 hrs after the last apix dose. ANNEXA™-R had 82 subjects treated with riva. AnXa (800 mg bolus; 800 mg bolus plus 8 mg/min x 2hr infusion) or placebo (2:1) was given on Day 4, 4 hrs after the last riva dose. Safety was followed through Day 43. Results: About 298 healthy subjects were enrolled in the studies. AnXa demonstrated rapid and sustained reversal of both direct and indirect fXa inhibitors as measured by correction of biomarkers. The ANNEXA™ studies confirmed findings from Phase 2, and met all primary (reversal of anti-fXa) and secondary endpoints (reduction of free inhibitor concentration and restoration of TG) with high statistical significance. AnXa was well-tolerated with no serious adverse events, thrombotic events, or antibodies to fX or fXa reported. Conclusion: AnXa treatment results in rapid and sustained reversal of anticoagulation of fXa inhibitors. A Phase 3b/4 confirmatory study (ANNEXA-4) in patients with acute major bleeds is ongoing.