INTEGRATE II: randomised phase III controlled trials of regorafenib containing regimens versus standard of care in refractory Advanced Gastro-Oesophageal Cancer (AGOC): a study by the Australasian Gastro-Intestinal Trials Group (AGITG).

BACKGROUND: Advanced gastro-oesophageal cancer (AGOC) carries a poor prognosis. No standard of care treatment options are available after first and second-line therapies. Regorafenib is an oral multi-targeted tyrosine kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinases. Regorafenib 160 mg daily prolonged progression free survival compared to placebo (INTEGRATE, phase 2). Regorafenib 80 mg daily in combination with nivolumab 3 mg/kg showed promising objective response rates (REGONIVO). METHODS/DESIGN: INTEGRATE II (INTEGRATE IIa and IIb) platform comprises two international phase III randomised controlled trials (RCT) with 2:1 randomisation in favor of experimental intervention. INTEGRATE IIa (double-blind) compares regorafenib 160 mg daily on days 1 to 21 of each 28-day cycle to placebo. INTEGRATE IIb (open label) compares REGONIVO, regorafenib 90 mg days 1 to 21 in combination with intravenous nivolumab 240 mg days 1 and 15 each 28-day cycle with investigator's choice of chemotherapy (control). Treatment continues until disease progression or intolerable adverse events as per protocol. Eligible participants include adults with AGOC who have failed two or more lines of treatment. Stratification is by location of tumour (INTEGRATE IIa only), geographic region, prior VEGF inhibitor and prior immunotherapy use (INTEGRATE IIb only). Primary endpoint is overall survival. Secondary endpoints are progression free survival, objective response rate, quality of life, and safety. Tertiary/correlative objectives include biomarker and pharmacokinetic evaluation. DISCUSSION: INTEGRATE II provides a platform to evaluate the clinical utility of regorafenib alone, as well as regorafenib in combination with nivolumab in treatment of participants with refractory AGOC. TRIAL REGISTRATION: INTEGRATE IIa prospectively registered 1 April 2016 Australia New Zealand Clinical Trial Registry: ACTRN12616000420448 (ClinicalTrials.gov NCT02773524). INTEGRATE IIb prospectively registered 10 May 2021 ClinicalTrials.gov: NCT04879368.

The Reemergence of Ketamine for Treatment in Critically Ill Adults.

OBJECTIVES: To assess the evidence and discuss the risks and clinical relevance of ketamine for the treatment of various disease states impacting the adult critically ill population. DATA SOURCES: A literature review was performed using PubMed evaluating primary literature published until August 2018. STUDY SELECTION: Case reports, observational studies (cohort, case-control), and randomized controlled trials involving patients 18 years and older in a nonperioperative setting using either IV or intramuscular ketamine were included for analysis. Uses of ketamine discussed focused on critically ill patients in the ICU and emergency department settings. DATA EXTRACTION: Included studies were evaluated for dosing, outcomes, and adverse effects of ketamine. For each study, the design, population, intervention, investigated outcomes, and results were assessed. DATA SYNTHESIS: The evidence was organized according to use of ketamine, which included pain, sedation, status asthmaticus, alcohol withdrawal syndrome, status epilepticus, and acute behavioral psychologic disturbances. Evaluation of the evidence was based on the included primary literature along with any related guideline recommendations. CONCLUSIONS: Ketamine has suggested potential benefit in several disease states impacting critically ill patients including pain, alcohol withdrawal syndrome, status epilepticus, and acute agitation. Further supporting evidence is needed to validate its use in the setting of critical illness.

25C-NBOMe Ingestion.

The popularity of recreational synthetic drug use has increased within the past several years. Emergency physicians, along with prehospital providers, are often the first to interact with patients who use these new drugs. We report the case of a 27-year-old male with two emergency department visits with confirmed ingestion of a relatively new synthetic drug of abuse. We discuss symptom management as well as the identification process of the ingestant.

Comparative Incidence of Nephrotoxicity by Age Group among Adult Patients Receiving Vancomycin.

INTRODUCTION: Little is known regarding age-related risk of nephrotoxicity during vancomycin therapy after the publication of the 2009 vancomycin consensus guidelines for therapeutic drug monitoring. We sought to evaluate incidence and risk factors for acute kidney injury in three age groups. METHODS: Matched cohort study of patients receiving vancomycin, grouped by age: young adults (18-64 years), older adults (65-79 years) and very elderly (≥80 years), matched on previously published risk factors for nephrotoxicity. Outcomes included traditional vancomycin nephrotoxicity and Acute Kidney Injury Network-modified definition of nephrotoxicity. RESULTS: The incidence of acute kidney injury was 34.1% vs. 34.1% vs. 31.8% in the young, older adults and very elderly groups, respectively (p = 0.97). In the logistic regression model, after adjusting for baseline risk factors, age was not a significant predictor of acute kidney injury. Lower respiratory tract infection (adjusted odds ratio [aOR] 5.18; 95% confidence interval [CI] 2.15-12.41) and duration of treatment (aOR 1.12; 95% CI 1.03-1.22) were found to be independently associated with outcome. CONCLUSION: No differences in risk of acute kidney injury were identified between young, older, and very elderly adults when adjusting for other risk factors. Further research is required to identify strategies to optimize the safety of vancomycin in the aging population.