Time Of First Dose Research Articles

Prophylactic antibiotic in general surgery

Objectives: To evaluate the role of antibiotic prophylaxis in general surgery with the incidence of wound infection and in comparison with extended regimen antibiotics.Methods: A prospective study of 150 patients were enrolled and operated upon electively which are divided into 2 groups. 100 patients were taking prophylactic antibiotics and 50 patients were on extended antibiotic regimen. Questionnaires concerning age, sex, type of surgery, complications and parameters of antibiotic prophylaxis (antibiotic choice, route, dose, timing of first dose and duration of prophylaxis) were completed.Results: Patients with prophylactic antibiotic, 79% of patients underwent a clean surgical operation and 21% underwent a clean contaminated operation. Inguinal hernia and open cholecystectomy were the commonest operation in each category, 4% of this group developing wound infection, also we take comparison with 50 cases in which we use extended antibiotic regimen Laparoscopic cholecystectomy and Para umbilical hernia were the commonest operations in this category, 6% of this group developing wound infection Ampicillin and cefotaxime were the most frequently prescribed antibiotics (50%, 50% respectively). All the 100 patients were received the antibiotic on time.Conclusions: This study found that the use of pre-operative prophylactic antibiotics does have a statistically significant effect on postoperative infection rates in surgical management.

Intrathecal nalbuphine vs. buprenorphine as an adjuvant in lower limb orthopedic surgeries: a prospective randomized controlled study.

This study aimed to compare the efficacy of intrathecal nalbuphine and buprenorphine as an adjuvant to heavy bupivacaine (0.5%) for spinal anesthesia in lower limb orthopedic surgeries to improve the quality of spinal anesthesia (onset, duration, and side effects) and prolongation of postoperative analgesia. Sixty patients were recruited into this single-centered, double-blinded, hospital-based, prospective, comparative study conducted in 2017–2018. They were randomly and equally (n = 30) allocated into two groups: nalbuphine group which received 0.5 mL (0.8 mg) of nalbuphine with 3 mL of heavy (0.5%) hyperbaric bupivacaine and buprenorphine group which received 0.5 mL (60 mg) of buprenorphine with 3 mL of heavy hyperbaric bupivacaine. Intraoperatively, onset and duration of blockade (motor and sensory), and time for first dose of rescue analgesia were recorded in both groups at regular intervals. Heart rate, blood pressure, Visual Analogue Scale score and side effects were also recorded postoperatively for 12 hours. The demographic parameters, time of onset of sensory block and motor block, and duration of motor block were comparable between nalbuphine and buprenorphine groups. The duration of sensory block in the buprenorphine group was longer than in the nalbuphine group. Time to the first dose of rescue analgesia was delayed in buprenorphine group as compared to nalbuphine group. In both groups maximum patients achieved maximum height of sensory block at 90 minutes. There were significant differences in the mean heart rate and blood pressure between buprenorphine and nalbuphine groups. Nalbuphine group patients achieved a Visual Analogue Scale score > 4 earlier as compared to buprenorphine group. Few side effects were observed in both groups. Intrathecal buprenorphine is a better adjuvant to 0.5% bupivacaine in the spinal anesthesia for lower limb orthopedic surgeries, as it provides longer sensory block and delayed administration of first dose of rescue analgesia with negligible side-effects. The study was approved by Institutional Ethics Committee of Krishna Institute of Medical Sciences (approval number: KIMSDU/IEC/03/2017) on November 23, 2017.

Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Preliminary Results of a Phase 2 Study of Camidanlumab Tesirine (Cami), a Novel Pyrrolobenzodiazepine-Based Antibody-Drug Conjugate, in Patients with Relapsed or Refractory Hodgkin Lymphoma

Comparative randomized study of continuous serratus anterior plane block versus continuous paravertebral block in post-mastectomy pain

BackgroundMany analgesic methods have been used to control post-mastectomy pain. Both thoracic paravertebral and serratus anterior blocks are recent regional techniques with promising results. The aim of this study was to compare safety and analgesic efficacy of both techniques in controlling post-mastectomy pain.MethodsThe study was conducted from January 1, 2019, till January 10, 2019, on 60 female patients ASA class ≤ 2 undergoing modified radical mastectomy. After induction of balanced general anesthesia patients received either continuous thoracic paravertebral block (group P) or continuous serratus anterior block (group S). Twenty milliliters of levobupivacaine 0.25% were injected in each technique under ultrasound guidance followed by continuous infusion of 5 ml/h levobupivacaine 0.125% through a 22-gage catheter. IV morphine was given postoperatively by patient-controlled analgesia. In both groups, we measured time to first dose morphine, total 24 and 48 h morphine consumption, vital signs, visual analog scale, and side effects of each technique.ResultsThe demographic data (age, body mass index, and duration of surgery) were comparable in both groups. The time for first dose of morphine was significantly longer in group P (368 ± 36 min) than group S (270 ± 37.65 min) with P value < 0.001. Total morphine consumption in milligram at both 24 and 48 h were significantly less in group P (8.1 ± 0.8, and 11.5 ± 1 respectively) than in group S (10.1 ± 1.3 and 14.2 ± 1.4), with limited side effects in both groups.ConclusionBoth continuous paravertebral and serratus anterior plane blocks are safe good alternatives to control post-mastectomy pain. However continuous paravertebral block provides better analgesic profile.

Veliparib (V) monotherapy after progression on placebo (PL) + carboplatin/paclitaxel (CP) in patients with advanced HER2-negative gBRCA-associated breast cancer: Crossover outcomes and exploratory biomarker analyses in BROCADE3.

1097 Background: In BROCADE3 (NCT02163694), addition of the PARP inhibitor (PARPi) V to CP improved PFS in patients (pts) with g BRCA-associated advanced breast cancer (hazard ratio 0.71 [95% CI 0.57–0.88], p = 0.002). Reversion mutations may account for resistance to platinum-based CT and PARPi. Efficacy, safety, and exploratory biomarker analyses for pts randomized to PL + CP who received crossover (Cx) V monotherapy after progression are reported. Methods: 513 total pts were randomized 2:1 to V + CP or PL + CP. V/PL, C, and P could be discontinued independently prior to progression, leading to varying platinum-free intervals at the time of progression. After progression, pts in the PL + CP arm could receive open-label Cx V monotherapy (300–400 mg BID continuous), beginning within 60 d of progression and continuing to second progression. Adverse events (AEs) and activity during Cx V were assessed. Exploratory analysis of BRCA reversion mutations restoring BRCA1/2 protein function that emerged during PL + CP treatment was performed on plasma circulating tumor DNA using targeted-amplicon next generation sequencing. Results: At data cutoff, 75 pts initially randomized to PL + CP had ≥1 dose of Cx V. Mean (range) duration of Cx V was 154 d (2–966). Activity during Cx V is in the Table. Mean (range) platinum-free interval at time of first dose of Cx V was 3.1 mos (0.4–10.9) vs 8.1 mos (1.0–34.9) in pts who had progressed vs had not progressed by 24 wks after first dose of Cx V. BRCA reversion analysis was completed for 18 Cx pts. Reversion mutations were identified in 1/18 pts (5.6%). This patient had Cx V duration of 19 d and had progressed by 24 wks. BRCA reversion analysis on additional Cx pts will be presented. Most common AEs during Cx V were nausea (61%), vomiting (29%), fatigue (24%), and diarrhea (21%). Any grade anemia, neutropenia, and thrombocytopenia occurred in 7%, 15%, and 7% of pts. Three pts (4%) experienced a convulsion event. Conclusions: Platinum-free interval may influence efficacy of subsequent PARPi. Impact of BRCA reversion mutations warrants further evaluation. Cross-resistance may limit PARPi efficacy after platinum failure. Clinical trial information: NCT02163694 . [Table: see text]

Edoxaban versus warfarin in vitamin K antagonist experienced and na\xefve patients from the edoxaban versus warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF) randomised trial

BackgroundIn ENSURE-AF study, edoxaban had similar efficacy and safety profile versus enoxaparin–warfarin (enox–warf) in patients undergoing electrical cardioversion of non-valvular atrial fibrillation.ObjectivesTo evaluate the efficacy and safety of edoxaban versus enox–warf in patients who were vitamin K antagonists (VKA) naïve or experienced at time of randomisation into ENSURE-AF trial.MethodsThe primary efficacy endpoint was a composite of stroke, systemic embolic event, myocardial infarction, and cardiovascular death during the overall study period, 28 days on study drug after cardioversion and 30 days follow-up. The primary safety endpoint was the composite of major and clinically relevant nonmajor bleeding during the on-medication period from time of first dose to last dose of study drug taken + 3 days.ResultsOf 2199 patients enrolled in ENSURE-AF, 1095 were randomised to edoxaban and 1104 to enox–warf. There were numerically fewer primary efficacy endpoint events with edoxaban than enox–warf irrespective of whether VKA experienced or naïve (0.5% vs. 0.9%, 0.3% vs. 1.4%, respectively). There were no significant differences in the primary safety endpoint [odds ratio (OR) 2.09, 95% confidence interval (CI) 0.72–6.81 in anticoagulant experienced patients, OR 0.77, 95% CI 0.15–3.60 in anticoagulant naïve patients] and in major bleeding rates regardless of treatment or VKA experience (OR 0.69, 95%CI 0.06–6.04, OR 0.48, 95% CI 0.01–9.25, respectively).ConclusionsEdoxaban had comparable efficacy and safety to optimized anticoagulation with enox–warf. The primary efficacy and safety endpoint outcomes were broadly similar between VKA experienced or naïve patients.

Effects of Varicella Vaccine Time of First Dose and Coverage of Second Dose - Beijing and Ningbo, China, 2012-2018.

What is already known about this topic?The effectiveness of the two-dose vaccination schedule of varicella is better than that of one dose, but the vaccination schedule and coverage of varicella varies based on provinces in the mainland of China and has differing effects.What is added by this report?Earlier vaccination of the first dose may reduce the varicella incidence, and improving the vaccination coverage rates of the second dose will further reduce the varicella incidence.What are the implications for public health practice?Taking the first dose of vaccination promptly at 12 months old and improving the coverage of second dose of vaccination may play an important role in varicella prevention and control in China.

Surgical antimicrobial prophylaxis prescribing practices and impact on infection risk: Results from a multicenter surveillance study in Italy (2012-2017)

Italy is one of the largest consumers of broad-spectrum agents (BSAs) in Europe. This study evaluated surgical antimicrobial prophylaxis (SAP) compliance with the Italian national guidelines and its impact on surgical site infection (SSI) risk. A prospective study was conducted in 42 hospitals participating in the national surveillance system for SSIs. SAP compliance was evaluated considering antibiotic choice, duration of administration, and timing of first dose. Trends in the consumption of 5 BSAs were also evaluated. Between 2012 and 2017, 24,861 surgical procedures were monitored. The risk ratios (RRs) for appropriate SAP increased by 22% each year, and significant increasing trends over time were found for overall compliance, timing, and duration. Adequate antibiotic choice and duration of administration were associated with a significantly reduced SSI risk (RR = 0.57; 95% confidence interval [CI], 0.5-0.65 vs RR = 0.51; 95% CI, 0.45-0.57, respectively), and overall compliance was associated with a RR of 0.65 (95% CI, 0.59-0.72). These findings suggest that appropriate narrow-spectrum agents could be more effective than BSAs in preventing SSIs. Interventions to improve SAP compliance with guidelines could significantly contribute to reducing antimicrobial resistance by reducing SSIs and promoting more prudent use of antimicrobials.

Initiation of sacubitril/valsartan in haemodynamically stabilised heart failure patients in hospital or early after discharge: primary results of the randomised TRANSITION study.

To assess tolerability and optimal time point for initiation of sacubitril/valsartan in patients stabilised after acute heart failure (AHF). TRANSITION was a randomised, multicentre, open-label study comparing two treatment initiation modalities of sacubitril/valsartan. Patients aged ≥ 18 years, hospitalised for AHF were stratified according to pre-admission use of renin-angiotensin-aldosterone system inhibitors and randomised (n=1002) after stabilisation to initiate sacubitril/valsartan either ≥ 12-h pre-discharge or between Days 1-14 post-discharge. Starting dose (as per label) was 24/26 mg or 49/51 mg bid with up- or down-titration based on tolerability. The primary endpoint was the proportion of patients attaining 97/103 mg bid target dose after 10weeks. Median time of first dose of sacubitril/valsartan from the day of discharge was Day -1 and Day +1 in the pre-discharge group and the post-discharge group, respectively. Comparable proportions of patients in the pre- and post-discharge initiation groups met the primary endpoint [45.4% vs. 50.7%; risk ratio (RR) 0.90; 95% confidence interval (CI) 0.79-1.02]. The proportion of patients who achieved and maintained for ≥ 2 weeks leading to Week 10, either 49/51 or 97/103 mg bid was 62.1% vs. 68.5% (RR 0.91; 95% CI 0.83-0.99); or any dose was 86.0% vs. 89.6% (RR 0.96; 95% CI 0.92-1.01). Discontinuation due to adverse events occurred in 7.3% vs. 4.9% of patients (RR 1.49; 95% CI 0.90-2.46). Initiation of sacubitril/valsartan in a wide range of heart failure with reduced ejection fraction patients stabilised after an AHF event, either in hospital or shortly after discharge, is feasible with about half of the patients achieving target dose within 10 weeks. ClinicalTrials.gov ID: NCT02661217.

Abstract P6-17-06: Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload

Abstract Background: Several classes of anti-cancer agents including certain immunotherapies, systemic chemotherapies, and targeted therapies including trastuzumab and T-DM1 increase the risk of interstitial lung disease (ILD) and fatal cases have been reported. For DS-8201a, interim efficacy and safety analyses of available data established a final recommended dose of 5.4 mg/kg IV q3wk in advanced HER2-positive breast cancer (BC). Based on preliminary clinical results, ILD was identified as an important risk for DS-8201a. A robust monitoring and management plan was established across all studies and an international, independent ILD adjudication committee (AC) reviews the cases reported as ILD on an ongoing basis. Methods: All subjects (sbj) who received ≥1 dose of DS-8201a across 7 ongoing studies were included in this analysis. Reported ILD (standardized MedDRA Query terms) included the terms ILD, pneumonitis, and organizing pneumonia. ILD frequencies were calculated based on investigator's assessment and after adjudication. The analysis of potential risk factors associated with ILD is ongoing. Results: As of 21 June 2018, 448 sbj received ≥1 dose of DS-8201a across multiple tumor types, including BC. Of the 321 sbj with BC, 173 (53.9%) were from Japan, 103 (32.1%) from the US, and 45 (14.0%) from 6 other countries (Spain, South Korea, Taiwan, Belgium, France, and Italy). These sbj received 1 of 7 doses of DS-8201a (0.8 mg/kg: 3 sbjs, 1.6 mg/kg: 1 sbj, 3.2 mg/kg: 3 sbjs, 5.4 mg/kg: 111 sbjs, 6.4 mg/kg: 178 sbj, 7.4 mg/kg: 20 sbj, 8.0 mg/kg: 5 sbj). Overall, 44 cases of potential ILD were reported by the investigators across all tumor types (44/448, 9.8%; Grade ≥3 10/448, 2.2%). In sbj with BC who received 5.4 mg/kg, any grade and Grade ≥3 investigator-reported ILD were 7.2% (8/111) and 0.9% (1/111), respectively. The ILD AC assessed 30 of 44 cases; 22 were considered drug-related ILD, 4 were ILD but not drug-related, and 4 were found not to be ILD. For adjudicated drug-related ILD cases, the median time to onset was 159 (range; 46-591) days from the time of first dose. Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 All Grades All tumors, All doses (N=448) Investigator-reported20 (4.5)14 (3.1)4 (0.9)1 (0.2)5 (1.1)44 (9.8)Cases adjudicated13840530Adjudicated as drug-related ILD9 (2.0)6 (1.3)3 (0.7)04 (0.9)22 (4.9) BC, All doses (N=321) Investigator-reported17 (5.3)11 (3.4)3 (0.9)1 (0.3)4 (1.2)36 (11.2)Cases adjudicated11830426Adjudicated as drug-related ILD8 (2.5)6 (1.9)3 (0.9)04 (1.2)21 (6.5) BC, 5.4 mg/kg (N=111) Investigator-reported4 (3.6)3 (2.7)001 (0.9)8 (7.2)Cases adjudicated120014Adjudicated as drug-related ILD00001 (0.9)1 (0.9)n (%), except where noted Conclusions: These analyses confirm that ILD is an important identified risk for DS-8201a. Further analyses are ongoing to better understand the potential risk factors associated with the incidence of on-treatment ILD. When ILD is suspected, early diagnosis through appropriate imaging, laboratory tests, and pulmonary consultation as well as prompt management with steroids are recommended. Citation Format: Powell CA, Camidge DR, Gemma A, Kusumoto M, Baba T, Kuwano K, Bankier A, Kiura K, Tamura K, Modi S, Tsurutani J, Doi T, Iwata H, Krop IE, Zhang L, Jasmeet S, Saito K, Shahidi J, Yver A, Takahashi S. Characterization, monitoring and management of interstitial lung disease in patients with metastatic breast cancer: Analysis of data available from multiple studies of DS-8201a, a HER2-targeted antibody drug conjugate with a topoisomerase I inhibitor payload [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-17-06.

391 Paralysis Following Acute Organophosphate Poisoning Improves Survival and Decreases Pulmonary Secretion Production in a Rat Model

Acute organophosphate poisoning (OP) produces profound pulmonary secretions. Standard treatment therapy includes anticholinergic medications aimed to reduce the volume of pulmonary secretion and mechanical ventilation for pulmonary support. Neuromuscular weakness termed intermediate syndrome attributes to morbidity and mortality related to OP poisoning in about 25% of cases. We have previously found that adding pancuronium to comprehensive medical treatment can preserve nicotinic acetylcholine receptors at the neuromuscular junction. The ideal timing of the first dose of pancuronium may have profound impacts on survival. Our objective was to compare the survival rates following acute OP poisoning in a rats model. Rats were intubated, anesthetized with isoflurane, and ventilated on a mechanical ventilator prior to exposure to intravenous OP (parathion 40mg/kg). Paralysis was initiated at 1, 4 and 7 hours post OP poisoning. Oxygenation saturation, pulse rate, and end-tidal CO2, peak inspiratory pressure (PIP), lung capacity (LC), and lung elastance (LE) were continuously monitored. Treatment with 2-PAM (90 mg/kg), midazolam (0.125mg/kg) and atropine (0.25mg/kg) were initiated at 1) point where pulse rate fell by 25% or 2) 40 minutes post poisoning. 2-PAM was repeated at 6 and 12 hours. Animals remained mechanically ventilated for 16 hours with atropine dosage titrated to volume of pulmonary secretions. All rats received equivalent medications, ventilator support and suctioning practices during the experiment. Pulmonary secretion volume was recorded using graduated suction catheters. Our study was powered to determine a 50% difference in mortality between groups with 10 animals in each group and 23% mortality difference with 22 animals in each group. Overall survival was higher when paralysis was initiated earlier. Baseline physiologic variables did not differ between study groups at the baseline period prior to poisoning. Animals paralyzed at 1 (n=10) and 4 hours (n=11) demonstrated 100% survival, but animals paralyzed at hour 7 hours (n=22) demonstrated 63.6% survival (p=0.035). Prominent respiratory secretions were seen in all animals post poisoning, but secretions were increased in group 3 with delayed paralysis. The average pulmonary secretion volume for each group is in Table 1. Animals with increased volume of pulmonary secretions were treated with higher doses of atropine.Tabled 1Average total pulmonary secretion volume (ul) and total atropine dose (mg) administered in 16 hourGroup 1: 1hr*Group 2: 4hr*Group 3: 7hr*Total Volume of Pulmonary Secretions (ul)122.95123.68276.82Total Atropine Dose1.741.732.17* Delay time of first dose of pancuronium (10mg/kg) Open table in a new tab * Delay time of first dose of pancuronium (10mg/kg)

Effectiveness of catch-up human papillomavirus vaccination on incident cervical neoplasia in a US health-care setting: a population-based case-control study

The population effectiveness of human papillomavirus (HPV) catch-up vaccination, defined in the USA as first vaccination at ages 13-26 years, has not been studied extensively. We aimed to assess the risk of cervical intraepithelial neoplasia (CIN) 2, CIN3, adenocarcinoma in situ, or cancer (CIN2+ and CIN3+) by prior HPV vaccination status, age at first dose, and number of doses in women participating in a screening programme within a large integrated health-care system. We performed a nested case-control study of women enrolled in Kaiser Permanente Northern California (an integrated health-care delivery system in California, USA). Cases were women with CIN2+ or CIN3+ confirmed by histology between Jan 1, 1995, and June 30, 2014, and incidence density-selected controls were age-matched women without CIN2+ or CIN3+ at the time each case occurred. For each case, we randomly selected five controls. Cases and controls were aged 26 years or younger when the HPV quadrivalent vaccine became available in 2006. Rate ratios (RRs) from conditional logistic regression were estimated by age at time of first HPV quadrivalent vaccine dose (14-17 years, 18-20 years, and ≥21 years), and number of doses (one, two, and three or more doses) compared with no prior vaccination, with adjustment for smoking, hormonal contraceptive prescription, race or ethnicity, sexually transmitted infections, immunosuppression, parity, and number of outpatient visits. 4357 incident CIN2+ cases and 21 773 matched controls were included in the study. Of these, 1849 were incident CIN3+ cases with 9242 matched controls. The youngest age at time of first vaccination was 14 years. One or more HPV vaccine doses conferred protection against CIN2+ (RR 0·82, 95% CI 0·73-0·93) and CIN3+ (0·77, 0·64-0·94). We found the strongest protection against CIN2+ in women who had received at least three vaccine doses and had received their first dose aged 14-17 years (0·52, 0·36-0·74) or aged 18-20 years (0·65, 0·49-0·88). No significant protection was found in women aged 21 years or older at time of first dose (0·94, 0·81-1·09). Inferences were similar for CIN3+, but with stronger effects for women who received at least three vaccine doses and had received their first dose aged 14-17 years (0·27, 0·13-0·56) or aged 18-20 years (0·59, 0·36-0·97). Catch-up quadrivalent HPV vaccination with three doses was effective against CIN2+ and CIN3+ in girls and women aged 14-20 years at time of first vaccine dose but not for women aged 21 years and older at first dose. US National Cancer Institute.

Human papillomavirus vaccination update: Nonavalent vaccine and the two-dose schedule.

Australia has included quadrivalent human papillomavirus (HPV) vaccination in its national program since 2007. Significant declines have been observed in the incidence of HPV infection, genital warts and high-grade cervical lesions. In 2018, the program changed to a nonavalent HPV vaccine administered over a routine two-dose schedule for the target cohort of adolescents aged 12-13 years. The aim of this article is to provide an overview of the nonavalent HPV vaccine, the rationale for its use and expected outcomes, and to review the updated dose scheduling requirements for HPV vaccines. The nonavalent HPV vaccine will broaden the impact of HPV vaccination, primarily against cervical cancer and pre-cancer. A two-dose schedule with an interval of 6-12 months between doses is appropriate for those aged ≤14 years at the time of first dose. Older individuals and those who are immunocompromised should continue to receive the three-dose schedule at zero, two and six months.

Early Intravascular Events Are Associated with Development of Acute Respiratory Distress Syndrome. A Substudy of the LIPS-A Clinical Trial.

Acute respiratory distress syndrome (ARDS) is a devastating illness with limited therapeutic options. A better understanding of early biochemical and immunological events in ARDS could inform the development of new preventive and treatment strategies. To determine select peripheral blood lipid mediator and leukocyte responses in patients at risk for ARDS. Patients at risk for ARDS were randomized as part of a multicenter, double-blind clinical trial of aspirin versus placebo (the LIPS-A [Lung Injury Prevention Study with Aspirin] trial; NCT01504867). Plasma thromboxane B2 (TXB2), aspirin-triggered lipoxin A4 (15-epi-LXA4, ATL), and peripheral blood leukocyte number and activation were determined on enrollment and after treatment with either aspirin or placebo. Thirty-three of 367 subjects (9.0%) developed ARDS after randomization. Baseline ATL levels, total monocyte counts, intermediate monocyte counts, and monocyte-platelet aggregates were associated with the development of ARDS. Peripheral blood neutrophil count and monocyte-platelet aggregates significantly decreased over time. Of note, nine subjects developed ARDS after randomization yet before study drug initiation, including seven subjects assigned to aspirin treatment. Subjects without ARDS at the time of first dose demonstrated a lower incidence of ARDS with aspirin treatment. Compared with placebo, aspirin significantly decreased TXB2 and increased the ATL/TXB2 ratio. Biomarkers of intravascular monocyte activation in at-risk patients were associated with development of ARDS. The potential clinical benefit of early aspirin for prevention of ARDS remains uncertain. Together, results of the biochemical and immunological analyses provide a window into the early pathogenesis of human ARDS and represent potential vascular biomarkers of ARDS risk. Clinical trial registered with www.clinicaltrials.gov (NCT01504867).

Abstract CT077: Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors

Abstract Introduction: Prior to the introduction of immunotherapies, treatment options were limited for patients (pts) with NSCLC who progressed after first-line platinum doublet chemotherapy. The majority of pts with advanced disease died within 1 y of diagnosis, and 5-y survival for metastatic NSCLC was ~1%. Nivolumab, a programmed death-1 (PD-1) immune checkpoint inhibitor antibody, showed encouraging activity in pts with heavily pretreated advanced NSCLC in a phase 1 dose-escalation cohort expansion trial (CA209-003; NCT00730639). Based on improved overall survival (OS) versus docetaxel in 2 phase 3 studies in previously treated advanced NSCLC (CheckMate 017 and 057), nivolumab was approved in this population. Reports of long-term efficacy and safety with immune checkpoint inhibitors are limited. Here we report updated results from CA209-003 based on ~5 y of follow-up, representing the longest survival follow-up for an immune checkpoint inhibitor in advanced NSCLC to date. Methods: Pts with heavily pretreated (1-5 prior systemic regimens) advanced NSCLC received nivolumab (1, 3, or 10 mg/kg) every 2 wk in 8-wk cycles for up to 96 wk. The primary objective was safety and tolerability; secondary objectives included objective response rate and duration of response. OS from the time of first dose was an exploratory objective. The minimum follow-up for the current analysis was 58.25 mo. Results: At database lock, the Kaplan-Meier-estimated 5-y OS rate in all pts (N = 129) was 16% (95% confidence interval [CI]: 10, 23). OS rates at 5 y were similar in pts with squamous (SQ; n = 54; 16% [95% CI: 8, 28]) and non-SQ (n = 74; 15% [95% CI: 8, 25]) NSCLC (excludes 1 pt with unknown histology). Of the 16 pts who survived ≥5 y (median age: 61.5 y [range: 44, 80]), 9 pts were male and 12 were current smokers at baseline (2 former smokers; 2 unknown). In 10 evaluable pts, PD-1 ligand 1 (PD-L1) expression was ≥1% in 7 pts (≥50% in 5) and &amp;lt;1% in 3 pts. Nine of the 16 pts completed the maximum number of nivolumab cycles per protocol; the remainder discontinued due to adverse events (n = 4), disease progression (n = 2), and initiation of a new treatment regimen (n = 1). Twelve of the 16 pts achieved a partial response, and 2 pts each had stable disease (SD) and progressive disease (PD) as best overall response (BOR) to nivolumab. At 5 y, per investigator, 12 pts had received no further therapy after stopping nivolumab treatment and were without evidence of PD. Further details of the disease and treatment course in select pts will be presented. Conclusions: Nivolumab resulted in durable OS in a notable proportion of pts with pretreated advanced NSCLC, as demonstrated by a 5-y OS rate of 16%. Long-term survivors had diverse baseline and on-treatment characteristics including histology, PD-L1 expression level (including pts with &amp;lt;1% PD-L1), and BOR to nivolumab (including pts with SD/PD). Citation Format: Julie Brahmer, Leora Horn, David Jackman, David Spigel, Scott Antonia, Matthew Hellmann, John Powderly, Rebecca Heist, Lecia Sequist, David C. Smith, Philip Leming, William J. Geese, Dennis Yoon, Ang Li, Scott Gettinger. Five-year follow-up from the CA209-003 study of nivolumab in previously treated advanced non-small cell lung cancer (NSCLC): Clinical characteristics of long-term survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT077. doi:10.1158/1538-7445.AM2017-CT077

A collaborative intervention to improve surgical antibiotic prophylaxis in children: results from a prospective multicenter study

The use of surgical antibiotic prophylaxis (SAP) in children is poorly characterized. Our aim was to evaluate the effectiveness of a quality improvement (QI) intervention targeting SAP in children, by means of a multicenter prospective intervention study, with a before and after design. We prospectively investigated elective surgical procedures performed in children <18years, prior to the QI intervention, after the intervention and at 9-month follow-up. The primary outcomes were adherence to SAP indications and SAP appropriateness, defined considering antibiotic choice, timing of first dose and duration of administration. We compared SAP adherence and appropriateness prior the QI intervention, to the post-intervention and the follow-up. We considered patient and procedure characteristics as covariates in two logistic regression models to assess the effect of the QI intervention on SAP adherence and appropriateness. We collected information on 2383 procedures (pre-intervention: 784; post-intervention: 790; follow-up: 809). The QI intervention had a significant impact on the adherence to SAP indications (86.6% in the post-intervention, compared to 82.0% prior to the intervention; p<0.05), and on its appropriateness (35.7% compared to 19.9%; p<0.01). The impact of the intervention on SAP appropriateness was maintained at follow-up (38.3%; p<0.01 compared to pre-intervention). All components of SAP appropriateness significantly improved after the intervention and at follow-up. The logistic regression analyses confirmed the effect of intervention in improving adherence to SAP indications and appropriateness. Following the QI intervention, there was a significant improvement in quality of SAP in pediatric surgery, though more efforts are needed to increase SAP appropriateness.

Rivaroxaban for venous thromboembolism prevention after major orthopedic surgery: translating trial data into routine clinical practice.

An established standard of care for the prevention of venous thromboembolism after major orthopedic surgery has been subcutaneous low-molecular-weight heparin. The non-vitamin K antagonist oral anticoagulant rivaroxaban has demonstrated superior efficacy and similar safety to all tested regimens of enoxaparin in large Phase III clinical studies of venous thromboembolism prevention after elective hip and knee arthroplasty. Despite regulatory approval of rivaroxaban for this indication, concerns remain among physicians regarding its optimal and effective use in routine clinical practice. Real-life studies, such as XAMOS and ORTHO-TEP, are providing physicians with more information on the routine use of rivaroxaban for venous thromboembolism prevention after orthopedic surgery, helping to establish its safety and effectiveness in everyday clinical care. Among the most important issues are the risk of bleeding complications, wound healing, timing of first dose, impact of type of anesthesia on thromboprophylaxis effectiveness, patient comorbidities and comedication use, periprocedural management, associated costs, and clinical outcomes in trauma-related fractures. Many of these issues are difficult to study in randomized, double-blind, Phase III trials, and can be assessed more readily using real-life data. In particular, real-life or noninterventional studies lack many of the strict inclusion and exclusion criteria associated with Phase III trials and involve unselected patients who often present with significant comorbidities or comedication use.

Effect of intravenous vitamin C on postoperative pain in uvulopalatopharyngoplasty with tonsillectomy.

Postoperative pain is a common problem in hospitals. Adults undergoing uvulopalatopharyngoplasty (UPPP) with tonsillectomy experience an unacceptable level of intense postoperative pain, especially during the first 24 h after surgery. This study investigated the analgesic effects of vitamin C in patients undergoing UPPP and tonsillectomy. This study was done on forty patients that were evaluated in a randomised double-blinded clinical trial. Patients included in the study were within the age range of 25-50 years with BMI<35, physical status I,II according to the American Society of Anesthesia (ASA) and who underwent uvulopalatopharyngoplasty and tonsillectomy. Patients with epilepsy, BMI>35, any neuropsychiatric disorders, a history of chronic pain, liver and/or renal disease, drug allergy, and drug abuse were excluded from the study. All patients underwent the same method of anaesthesia and surgical procedure. During the first 30 min after the beginning of the surgery, group C (vitamin C) received infusion of 3 g vitamin C in 500 mL of Ringer and group P received 6 mL normal saline in 500 mL of Ringer. Measurements of systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate were recorded before and during anaesthesia and at intervals of 0,15,30 and 60 min after extubation. Pain severity was recorded according to VAS score at intervals of 0 (recovery room), 6, 12 and 24 h after the procedure, request for analgesic drugs (iv paracetamol or pethedine) according to total number of times of analgesic request and time of the first dose of analgesic use and dose of pethidine were also recorded by questionnaire. There was a significant difference in evaluations for mean pain severity between the two groups at recovery room, 6, 12 and 24 h after surgery (P-value = 0.001). There was a significant difference in mean times that patient requested an analgesic, time of first dose of analgesic and pethidine dose between the two groups (P-value< 0.05). There was no significant differences in measurements of systolic blood pressure, diastolic blood pressure, mean arterial blood pressure and heart rate in different times between the two groups (P-value> 0.05). Blood loss was similar in the two groups (P-value> 0.05). According to this study, administration of vitamin C 3 g IV intraoperative reduced postoperative pain without increased side-effects in patients undergoing UPPP and tonsillectomy.

Abstract B23: Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab

Abstract Introduction: Autoimmune hypophysitis (AH) is an immune-related adverse effect (ir-AE) of the human IgG1 monoclonal antibody ipilimumab. Evidence suggests AH is mediated by complement deposition in adenohypophyseal cells expressing cytotoxic T lymphocyte antigen-4 (CTLA-4). Despite increasing incidence, AH remains poorly characterized. We conducted a retrospective cohort study of melanoma subjects treated with ipilimumab, with the primary objective to characterize AH and examine its association with overall survival (OS). Methods: Inclusion criteria: stage 3/4 cutaneous, ocular, or mucosal melanoma at a single institution, treated with ipilimumab between 2005 and 2013. AH was defined as primary hypopituitarism clinically diagnosed by endocrinologist or cutaneous oncologist. Baseline BMI and laboratory values were collected within 30 days prior to first dose. Overall survival (OS) was defined as time from first dose to death of any cause. Time-to-progression (TTP) was defined as time from first dose to any objective progression event, and censored if &amp;gt;4 months (mo) elapsed between evaluations to ensure homogenous follow-up time. Statistical tests were non-parametric and 2-sided. Results: Of 295 patients screened, 269 were eligible (32 AH+, 237 AH-). Demographics at first dose: median age 61.6, 35% female, 99.3% white, 1.9% Hispanic, mean body mass index (BMI) 28 kg/m2, mean lactate dehydrogenase (LDH) 644 IU/L, mean albumin 4.0 mg/dL, mean absolute lymphocyte count 1.39 x 103/μL. For TNM stage, 65% M1c, 14% M1b, 6% M1a, 15% M0. At time of first dose, 29.5% were resected no evidence-of-disease (NED). Of 132 (49%) with known allelic status, 38 (29%) were BRAF mutant. Median time-to-AH was 2.8 mo (range 0.9 – 18.7). Initial dose of 10 mg/kg was associated with increased AH risk (RR 1.2, p=0.002). Presenting symptoms included fatigue (58%), headache (33%), nausea (24%). Lab findings at diagnosis (median, range): ACTH 7.0 (1-26), cortisol 2.2 (0-29.7), TSH 0.34 (0-3.9), T4 0.7 (0.3 – 3.6), FSH 7.0 (1.1 – 41), LH 0.7 (0.2 – 20.5). 17 of 30 evaluable subjects had abnormal pituitary identified on MRI. All were administered exogenous corticosteroids and 72% required exogenous thyroid supplementation. 13% eventually recovered endogenous pituitary function. There was no association with prior endocrine conditions or other ir-AEs. For evaluable subjects, AH also seemed to have favorable objective response rate, although this was not statistically significant (p=0.20). Median follow-up duration was 43.7 mo, median OS was 20.3 mo, and median TTP was 5.2 mo. AH was associated with superior OS (HR 0.4, 95% CI 0.3 – 0.7, p=0.001) and TTP (HR 0.4, 95%CI 0.3- 0.8, p=0.0002). Using Landmark analysis to avoid bias from immortal person-time, after 4 cycles of ipilimumab, AH remained associated with OS (HR 0.5, p=0.04). Using the alternative Crowley method, similar results were seen for both OS (HR 0.5, p=0.002) and TTP (HR 0.6, p=0.005). AH was then examined as a time-dependent covariate in Cox regression. On univariate analysis, LDH, M-stage, resected NED, albumin, age, absolute lymphocyte count, and AH were significantly associated with OS (p &amp;lt;0.01 for all). Similar findings were found for TTP. After including a propensity score regression term to control for all known confounders (LDH, albumin, BMI, lymphocyte count, M-stage, NED, smoking, race, age, gender), AH remained an independent predictor for improved OS (HR 0.49;95%CI 0.24-0.98; p=0.04). Conclusion: Hypophysitis appears to predict benefit from ipilimumab treatment, possibly since it may serve as a marker of cellular immune activation. Independent validation of these results in external cohorts is required. Citation Format: Jennifer M. Eatrides, Jeffrey Weber, Kathleen Egan, Marjorie Acierno, Michael Schell, Howard Lillienfeld, Ben Creelan. Autoimmune hypophysitis is a marker of favorable outcome during treatment of melanoma with ipilimumab. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Melanoma: From Biology to Therapy; Sep 20-23, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(14 Suppl):Abstract nr B23.

Clinician response time for positive blood culture results in a pediatric ICU

IntroductionPositive blood cultures guide clinicians to prescribe specific therapy based on in vitro susceptibility. Delays in appropriate antibiotic therapy increase morbidity associated with positive blood culture. HypothesisTime from clinician notification of positive blood culture to administration of targeted antimicrobial therapy should follow Surviving Sepsis guidelines. MethodsStudy setting was a 44 bed pediatric ICU. Data were extracted from the pharmacy database and the medical records of pediatric ICU patients with positive blood culture. Source, time blood culture was obtained, time of clinician notification of positive result, and administration time of first dose of new antimicrobial was captured. Results174 positive blood cultures from 111 PICU patients were examined. Antimicrobials were changed after the positive culture in 51 (49%) patients. The new antibiotic was administered in an average of 6 h 35 min from clinician notification. ConclusionsWe demonstrated a delay from clinician notification of positive culture to new antibiotic administration.