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.

Prevalence and Predictors of Long-term Opioid Use After Pelvic Fractures.

BACKGROUND: Opioids are effective in short-term pain treatment; however, their long-term effectiveness is unconfirmed. Many patients are exposed to opioids after pelvic injuries with little known about persistent use afterward. We assessed the prevalence and predictors of long-term opioid use following pelvic fractures. MATERIALS AND METHODS: This retrospective study enrolled 277 patients with acute pelvic fractures over five years. Daily and total morphine milligram equivalents (MME) were calculated. The primary outcome was long-term opioid use (LOU) defined as ongoing opioid use 60-90 days post-discharge. The secondary outcome was intermediate-term opioid use (IOU) defined as ongoing opioid use 30-60 days post-discharge. Univariable and logistic regression analyses were performed. RESULTS: Median (interquartile range) total inpatient opioid MME was 422 (157-1667) with a median daily MME of 69 (26-145). Long-term opioid use occurred in 16%, and IOU occurred in 29%. Univariable analysis found that total and daily inpatient opioid use were each significantly associated with LOU (median MME, 1241 vs 371; median MMEs, 127.7 vs 59.2, respectively) and IOU (median MME, 1140 vs 326; median MMEs, 111.8 vs 57.9, respectively). Logistic regression analysis found daily inpatient MME ≥50 (odds ratio [OR] 3.027, 95% confidence interval [CI] 1.059-8.652]) and pelvic fracture type (Tile B/C) (OR 2.992 [CI 1.324-6.763])were independent predictors of LOU. CONCLUSION: Total and daily inpatient opioid use were significantly associated with LOU and IOU. Patients who received ≥50 MME/inpatient day had a higher likelihood of LOU. This study seeks to inform clinical decisions for pain management to prevent adverse outcomes.

Hospital-diagnosed infections with Escherichia coli clonal group ST131 are mostly acquired in the community.

The worldwide spread of E. coli ST131 has significantly contributed to the dissemination of E. coli producing extended-spectrum ß-lactamases (ESBL). In a French University hospital, we assessed the molecular features of ESBL-producing E. coli and identified risk factors in patients for colonization or infection with E. coli ST131. Over a 2-year period (2015-2017), each patient with at least one clinical isolate or one screening isolate positive with ESBL-producing E. coli were included (n = 491). The ST131 clonal group accounted for 17.5% (n = 86) of all ESBL-producing E. coli and represented 57.3% isolates of phylogroup B2. FimH-based sub-typing showed that 79.1% (68/86) of ST131 isolates were fimH30, among which 67.6% (n = 46), 20.6% (n = 14) and 11.8% (n = 8) isolates harbored genes encoding the ESBL CTX-M-15, CTX-M-27, and CTX-M-14, respectively. The multivariate analysis identified two factors independently associated with ST131 ESBL-producing E. coli isolates: infection (Odds ratio [OR] = 1.887, 95% confidence interval [CI]: 1.143-3.115; p = 0.013) and community acquisition (OR = 2.220, 95% CI: 1.335-3.693; p = 0.002). In conclusion, our study confirmed the predominance of ST131 clonal group among ESBL-producing E. coli and the difficulty to identify common risk factors associated with carriage of this pandemic clonal group.

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.

An unexpected clinical course in a 29-day-old infant with ethanol exposure.

Ethanol exposure can affect all pediatric age groups but occurs most commonly in ambulatory children and adolescents. Infants are less likely to ingest ethanol because they have limited ability to explore their environments. However, ethanol exposures in infants can occur. We report the case of a 29-day-old (3.5 kg) baby girl who presented with a blood alcohol level of 301 mg/dL after ingesting formula that had been prepared with gin. To our knowledge, she is the youngest reported child with such an elevated ethanol level in the medical literature. Despite her markedly elevated blood alcohol level, she had an unexpectedly mild clinical course, exhibiting subtle neurologic symptoms but no hypothermia, hypoglycemia, or cardiorespiratory impairment. This case demonstrates that the ethanol-exposed infant may lack typical or clear symptoms of acute intoxication. Therefore, the clinician must have a low threshold for pursuing blood alcohol testing in infants and young children with altered mental status. A prompt diagnosis of ethanol exposure is important for ensuring the health and safety of the child.

Comparison of toxicity of acute overdoses with citalopram and escitalopram.

BACKGROUND: Seizures and QTc prolongation are associated with citalopram poisoning; however, overdose experience with escitalopram is more limited. OBJECTIVES: The goals of this study were to compare citalopram's vs. escitalopram's clinical effects in overdose, including the incidence of seizures. METHODS: A retrospective review was conducted for single-substance acute overdoses with citalopram and escitalopram, managed in hospitals, that were reported to six U.S. poison centers from 2002-2005. RESULTS: There were 374 citalopram and 421 escitalopram overdose cases. Gender and ages were similar between the two, with 68-70% females and a median age of 20 years for citalopram and 18 years for escitalopram. Median dose by history was 310 mg for citalopram and 130 mg for escitalopram. More serious outcomes were associated with citalopram overdoses (p < 0.001). Most frequently reported clinical effects with citalopram and escitalopram were tachycardia, drowsiness, hypertension, and vomiting. Seizures (30 vs. 1, respectively, p < 0.001) and tremor (32 vs. 13, respectively, p = 0.001) were more common with citalopram. QTc prolongation occurred in 14 citalopram cases and 7 escitalopram cases (p = 0.109). There was an association between increasing dose and severity of outcome for citalopram (p < 0.001) and escitalopram (p = 0.011). In children < 6 years old, 12 of 66 citalopram and 5 of 57 escitalopram cases experienced toxicity, such as drowsiness, nausea/vomiting, and tachycardia. There were no seizures in this age group. CONCLUSIONS: Escitalopram seems to be less toxic than citalopram after an acute overdose; seizures and tremors were more common with citalopram. Initial management of overdoses should include seizure precautions for citalopram and cardiac monitoring for both drugs.

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.