Evaluation of the interest to combine a CD4 Th1-inducer cancer vaccine derived from telomerase and atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma: a randomized non-comparative phase II study (TERTIO - PRODIGE 82).

BACKGROUND: Several cancer immunotherapies that target the PD-L1/PD-1 pathway show promising clinical activity in patients with hepatocellular carcinoma (HCC). However, the standard of care in first-line treatment with atezolizumab (anti-PD-L1 therapy) in combination with bevacizumab is associated with a limited objective response rate. Telomerase reverse transcriptase (TERT) activation meets the criteria of oncogenic addiction in HCC and could be actionable therapeutic target and a relevant tumor antigen. Therefore we hypothesized that combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine might be an attractive therapy in HCC. UCPVax is a therapeutic cancer vaccine composed of two separate peptides derived from telomerase (human TERT). UCPVax has been evaluated in a multicenter phase I/II study in non-small cell lung cancers and has demonstrated to be safe and immunogenic, and is under evaluation in combination with atezolizumab in a phase II clinical trial in tumors where telomerase reactivation contributes to an oncogene addiction (HPV+ cancers). The aim of the TERTIO study is to determine the clinical interest and immunological efficacy of a treatment combining the CD4 helper T-inducer cancer anti-telomerase vaccine (UCPVax) with atezolizumab and bevacizumab in unresectable HCC in a multicenter randomized phase II study. METHODS: Patients with locally advanced, metastatic or unresectable HCC who have not previously received systemic anti-cancer treatment are eligible. The primary end point is the objective response rate at 6 months. Patients will be allocated to a treatment arm with a randomization 2:1. In both arms, patients will receive atezolizumab at fixed dose of 1200 mg IV infusion and bevacizumab at fixed dose of 15 mg/kg IV infusion, every 3 weeks, according to the standard of care. In the experimental arm, these treatments will be combined with the UCPVax vaccine at 0.5 mg subcutaneously. DISCUSSION: Combining anti-PD-1/PD-L1 therapy with an anti-telomerase vaccine gains serious consideration in HCC, in order to extend the clinical efficacy of anti-PD-1/PD-L1. Indeed, anti-cancer vaccines can induce tumor-specific T cell expansion and activation and therefore restore the cancer-immunity cycle in patients lacking pre-existing anti-tumor responses. Thus, there is a strong rational to combine immune checkpoint blockade therapy and anticancer vaccine (UCPVax) in order to activate antitumor T cell immunity and bypass the immunosuppression in the tumor microenvironment in HCC. This pivotal proof of concept study will evaluate the efficacy and safety of the combination of a CD4 Th1-inducer cancer vaccine derived from telomerase (UCPVax) and atezolizumab plus bevacizumab in unresectable HCC, as well as confirming their synergic mechanism, and settling the basis for a new combination for future clinical trials. TRIAL REGISTRATION: NCT05528952.

Higher third-generation cephalosporin prescription proportion is associated with lower probability of reducing carbapenem use: a nationwide retrospective study.

Background: The ongoing extended spectrum ß-lactamase-producing Enterobacteriaceae (ESBL-PE) pandemic has led to an increasing carbapenem use, requiring release of guidelines for carbapenem usage in France in late 2010. We sought to determine factors associated with changes in carbapenem use in intensive care units (ICUs), medical and surgical wards between 2009 and 2013. Methods: This ward-level multicentre retrospective study was based on data from French antibiotic and multidrug-resistant bacteria surveillance networks in healthcare facilities. Antibiotic use was expressed in defined daily doses per 1000 patient-days. Factors associated with the reduction in carbapenem use (yes/no) over the study period were determined from random-effects logistic regression model (493 wards nested within 259 healthcare facilities): ward characteristics (type, size…), ward antibiotic use (initial antibiotic use [i.e., consumption of a given antibiotic in 2009], initial antibiotic prescribing profile [i.e., proportion of a given antibiotic in the overall antibiotic consumption in 2009] and reduction in the use of a given antibiotic between 2009 and 2013) and regional ESBL-PE incidence rate in acute care settings in 2011. Results: Over the study period, carbapenem consumption in ICUs (n = 85), medical (n = 227) and surgical wards (n = 181) was equal to 73.4, 6.2 and 5.4 defined daily doses per 1000 patient-days, respectively. Release of guidelines was followed by a significant decrease in carbapenem use within ICUs and medical wards, and a slowdown in use within surgical wards. The following factors were independently associated with a higher probability of reducing carbapenem use: location in Eastern France, higher initial carbapenem prescribing profile and reductions in consumption of fluoroquinolones, glycopeptides and piperacillin/tazobactam. In parallel, factors independently associated with a lower probability of reducing carbapenem use were ICUs, ward size increase, wards of cancer centres, higher initial third-generation cephalosporin (3GC) prescribing profile and location in high-risk regions for ESBL-PE. Conclusions: Our study suggests that a decrease in 3GCs in the overall antibiotic use and the continuation of reduction in fluoroquinolone use, could allow reducing carbapenem use, given the well-demonstrated role of 3GCs and fluoroquinolones in the occurrence of ESBL-PE. Thus, antibiotic stewardship programs should target wards with higher 3GC prescription proportions to reduce them.

Surgical antibiotic prophylaxis compliance in a university hospital.

OBJECTIVE: To assess surgical antibiotic prophylaxis (SAP) practices in a university hospital in order to identify risk factors associated with non-compliance. STUDY DESIGN: Retrospective monocentric study conducted over a 4-month period. PATIENTS AND METHODS: Data were collected from the software used in the operating theatre. Practice non-compliance was evaluated in comparison with the 2010 version of the French national recommendations. We only took in account the interventions identified as priority surveillance interventions according to the surgical site infections national surveillance. The risk factors associated with SAP non-compliance were identified with a multivariate statistical analysis. RESULTS: We evaluated 1312 SAPs. Among the 1298 indicated SAPs, 44.4% were not compliant. The most frequent inappropriate criterion was the timing of injection (34.8% non-compliance), which was, in the majority of cases, too close to the time of incision. Other inappropriate criteria were identified: antibiotic choice for patients allergic to ß-lactams (inappropriate among 45% of allergic patients), and antibiotic dosing for obese patients (96% of non-compliance). Obesity (OR=84.32), allergy to ß-lactams (OR=17.11) and certain types of surgery (digestive, OR=4.56; gynaecological and obstetrical, OR=7.10; urological, OR=3.95) were independently associated with the non-compliance of SAP practices. CONCLUSION: Improvement measures that target the timing of injection, obese or allergic patients are necessary.

Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine.

Animal studies show efficacy of intravenous lipid emulsion in the treatment of severe cardiotoxicity associated with local anesthetics, clomipramine, and verapamil, possibly by trapping such lipophilic drugs in an expanded plasma lipid compartment ("lipid sink"). Recent case reports describe lipid infusion for the successful treatment of refractory cardiac arrest caused by parenteral administration of local anesthetics, but clinical evidence has been lacking for lipid's antidotal efficacy on toxicity caused by ingested medications. A 17-year-old girl developed seizure activity and cardiovascular collapse after intentional ingestion of up to 7.95 g of bupropion and 4 g of lamotrigine. Standard cardiopulmonary resuscitation for 70 minutes was unsuccessful in restoring sustained circulation. A 100-mL intravenous bolus of 20% lipid emulsion was then administered, and after 1 minute an effective sustained pulse was observed. The patient subsequently manifested significant acute lung injury but had rapid improvement in cardiovascular status and recovered, with near-normal neurologic function. Serum bupropion levels before and after lipid infusion paralleled triglyceride levels. This patient developed cardiovascular collapse because of intentional, oral overdose of bupropion and lamotrigine that was initially refractory to standard resuscitation measures. An infusion of lipid emulsion was followed rapidly by restoration of effective circulation. Toxicologic studies are consistent with the lipid sink theory of antidotal efficacy.