Jean-Paul Mira

Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy

Conventional cancer treatments rely on radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Here we show that the success of some protocols for anticancer therapy depends on innate and adaptive antitumor immune responses. We describe in both mice and humans a previously unrecognized pathway for the activation of tumor antigen–specific T-cell immunity that involves secretion of the high-mobility-group box 1 (HMGB1) alarmin protein by dying tumor cells and the action of HMGB1 on Toll-like receptor 4 (TLR4) expressed by dendritic cells (DCs). During chemotherapy or radiotherapy, DCs require signaling through TLR4 and its adaptor MyD88 for efficient processing and cross-presentation of antigen from dying tumor cells. Patients with breast cancer who carry a TLR4 loss-of-function allele relapse more quickly after radiotherapy and chemotherapy than those carrying the normal TLR4 allele. These results delineate a clinically relevant immunoadjuvant pathway triggered by tumor cell death.

High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure

BACKGROUND Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia. METHODS We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28. RESULTS A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006). CONCLUSIONS In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.).

Epidemiology, management, and risk factors for death of invasive candida infections in critical care: A multicenter, prospective, observational study in France (2005–2006)

Objective:To describe the evolving epidemiology, management, and risk factors for death of invasive Candida infections in intensive care units (ICUs). Design:Prospective, observational, national, multicenter study. Setting:One hundred eighty ICUs in France. Patients:Between October 2005 and May 2006, 300 adult patients with proven invasive Candida infection who received systemic antifungal therapy were included. Interventions:None. Measurements and Main Results:One hundred seven patients (39.5%) with isolated candidemia, 87 (32.1%) with invasive candidiasis without documented candidemia, and 77 (28.4%) with invasive candidiasis and candidemia were eligible. In 37% of the cases, candidemia occurred within the first 5 days after ICU admission. C. albicans accounted for 57.0% of the isolates, followed by C. glabrata (16.7%), C. parapsilosis (7.5%), C. krusei (5.2%), and C. tropicalis (4.9%). In 17.1% of the isolates, the causative Candida was less susceptible or resistant to fluconazole. Fluconazole was the empirical treatment most commonly introduced (65.7%), followed by caspofungin (18.1%), voriconazole (5.5%), and amphotericin B (3.7%). After identification of the causative species and susceptibility testing results, treatment was modified in 86 patients (31.7%). The case fatality ratio in ICU was 45.9% and did not differ significantly according to the type of episode. Multivariate analysis showed that factors independently associated with death in ICU were type 1 diabetes mellitus (odds ratio [OR] 4.51; 95% confidence interval [CI] 1.72–11.79; p = 0.002), immunosuppression (OR 2.63; 95% CI 1.35–5.11; p = 0.0045), mechanical ventilation (OR 2.54; 95% CI 1.33–4.82; p = 0.0045), and body temperature >38.2°C (reference, 36.5–38.2°C; OR 0.36; 95% CI 0.17–0.77; p = 0.008). Conclusions:More than two thirds of patients with invasive candidiasis in ICU present with candidemia. Non-albicans Candida species reach almost half of the Candida isolates. Reduced susceptibility to fluconazole is observed in 17.1% of Candida isolates. Mortality of invasive candidiasis in ICU remains high.

High versus Low Blood-Pressure Target in Patients with Septic Shock

BACKGROUND The Surviving Sepsis Campaign recommends targeting a mean arterial pressure of at least 65 mm Hg during initial resuscitation of patients with septic shock. However, whether this blood-pressure target is more or less effective than a higher target is unknown. METHODS In a multicenter, open-label trial, we randomly assigned 776 patients with septic shock to undergo resuscitation with a mean arterial pressure target of either 80 to 85 mm Hg (high-target group) or 65 to 70 mm Hg (low-target group). The primary end point was mortality at day 28. RESULTS At 28 days, there was no significant between-group difference in mortality, with deaths reported in 142 of 388 patients in the high-target group (36.6%) and 132 of 388 patients in the low-target group (34.0%) (hazard ratio in the high-target group, 1.07; 95% confidence interval [CI], 0.84 to 1.38; P=0.57). There was also no significant difference in mortality at 90 days, with 170 deaths (43.8%) and 164 deaths (42.3%), respectively (hazard ratio, 1.04; 95% CI, 0.83 to 1.30; P=0.74). The occurrence of serious adverse events did not differ significantly between the two groups (74 events [19.1%] and 69 events [17.8%], respectively; P=0.64). However, the incidence of newly diagnosed atrial fibrillation was higher in the high-target group than in the low-target group. Among patients with chronic hypertension, those in the high-target group required less renal-replacement therapy than did those in the low-target group, but such therapy was not associated with a difference in mortality. CONCLUSIONS Targeting a mean arterial pressure of 80 to 85 mm Hg, as compared with 65 to 70 mm Hg, in patients with septic shock undergoing resuscitation did not result in significant differences in mortality at either 28 or 90 days. (Funded by the French Ministry of Health; SEPSISPAM ClinicalTrials.gov number, NCT01149278.).

Immediate Percutaneous Coronary Intervention Is Associated With Better Survival After Out-of-Hospital Cardiac Arrest Insights From the PROCAT (Parisian Region Out of Hospital Cardiac Arrest) Registry

Background— Acute coronary occlusion is the leading cause of cardiac arrest. Because of limited data, the indications and timing of coronary angiography and angioplasty in patients with out-of-hospital cardiac arrest are controversial. Using data from the Parisian Region Out of hospital Cardiac ArresT prospective registry, we performed an analysis to assess the effect of an invasive strategy on hospital survival. Methods and Results— Between January 2003 and December 2008, 714 patients with out-of-hospital cardiac arrest were referred to a tertiary center in Paris, France. In 435 patients with no obvious extracardiac cause of arrest, an immediate coronary angiogram was performed at admission followed, if indicated, by coronary angioplasty. At least 1 significant coronary artery lesion was found in 304 (70%) patients, in 128 (96%) of 134 patients with ST-segment elevation on the ECG performed after the return of spontaneous circulation, and in 176 (58%) of 301 patients without ST-segment elevation. The hospital survival rate was 40%. Multivariable analysis showed successful coronary angioplasty to be an independent predictive factor of survival, regardless of the postresuscitation ECG pattern (odds ratio, 2.06; 95% CI, 1.16 to 3.66). Conclusions— Successful immediate coronary angioplasty is associated with improved hospital survival in patients with or without ST-segment elevation. Therefore, our findings support the use of immediate coronary angiography in patients with out-of-hospital cardiac arrest with no obvious noncardiac cause of arrest regardless of the ECG pattern.Background—Acute coronary occlusion is the leading cause of cardiac arrest. Because of limited data, the indications and timing of coronary angiography and angioplasty in patients with out-of-hospital cardiac arrest are controversial. Using data from the Parisian Region Out of hospital Cardiac ArresT prospective registry, we performed an analysis to assess the effect of an invasive strategy on hospital survival. Methods and Results—Between January 2003 and December 2008, 714 patients with out-of-hospital cardiac arrest were referred to a tertiary center in Paris, France. In 435 patients with no obvious extracardiac cause of arrest, an immediate coronary angiogram was performed at admission followed, if indicated, by coronary angioplasty. At least 1 significant coronary artery lesion was found in 304 (70%) patients, in 128 (96%) of 134 patients with ST-segment elevation on the ECG performed after the return of spontaneous circulation, and in 176 (58%) of 301 patients without ST-segment elevation. The hospital survival rate was 40%. Multivariable analysis showed successful coronary angioplasty to be an independent predictive factor of survival, regardless of the postresuscitation ECG pattern (odds ratio, 2.06; 95% CI, 1.16 to 3.66). Conclusions—Successful immediate coronary angioplasty is associated with improved hospital survival in patients with or without ST-segment elevation. Therefore, our findings support the use of immediate coronary angiography in patients with out-of-hospital cardiac arrest with no obvious noncardiac cause of arrest regardless of the ECG pattern.

The interaction between HMGB1 and TLR4 dictates the outcome of anticancer chemotherapy and radiotherapy.

Summary: For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor‐induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll‐like receptor 4 (TLR4) on DCs, which are selectively involved in the cross‐priming of anti‐tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline‐based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens.

Effect of Eritoran, an Antagonist of MD2-TLR4, on Mortality in Patients With Severe Sepsis: The ACCESS Randomized Trial

IMPORTANCE Eritoran is a synthetic lipid A antagonist that blocks lipopolysaccharide (LPS) from binding at the cell surface MD2-TLR4 receptor. LPS is a major component of the outer membrane of gram-negative bacteria and is a potent activator of the acute inflammatory response. OBJECTIVE To determine if eritoran, a TLR4 antagonist, would significantly reduce sepsis-induced mortality. DESIGN, SETTING, AND PARTICIPANTS We performed a randomized, double-blind, placebo-controlled, multinational phase 3 trial in 197 intensive care units. Patients were enrolled from June 2006 to September 2010 and final follow-up was completed in September 2011. INTERVENTIONS Patients with severe sepsis (n = 1961) were randomized and treated within 12 hours of onset of first organ dysfunction in a 2:1 ratio with a 6-day course of either eritoran tetrasodium (105 mg total) or placebo, with n = 1304 and n = 657 patients, respectively. MAIN OUTCOME MEASURES The primary end point was 28-day all-cause mortality. The secondary end points were all-cause mortality at 3, 6, and 12 months after beginning treatment. RESULTS Baseline characteristics of the 2 study groups were similar. In the modified intent-to-treat analysis (randomized patients who received at least 1 dose) there was no significant difference in the primary end point of 28-day all-cause mortality with 28.1% (366/1304) in the eritoran group vs 26.9% (177/657) in the placebo group (P = .59; hazard ratio, 1.05; 95% CI, 0.88-1.26; difference in mortality rate, -1.1; 95% CI, -5.3 to 3.1) or in the key secondary end point of 1-year all-cause mortality with 44.1% (290/657) in the eritoran group vs 43.3% (565/1304) in the placebo group, Kaplan-Meier analysis of time to death by 1 year, P = .79 (hazard ratio, 0.98; 0.85-1.13). No significant differences were observed in any of the prespecified subgroups. Adverse events, including secondary infection rates, did not differ between study groups. CONCLUSIONS AND RELEVANCE Among patients with severe sepsis, the use of eritoran, compared with placebo, did not result in reduced 28-day mortality. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00334828.

Immediate Percutaneous Coronary Intervention Is Associated With Better Survival After Out-of-Hospital Cardiac ArrestClinical Perspective

Background— Acute coronary occlusion is the leading cause of cardiac arrest. Because of limited data, the indications and timing of coronary angiography and angioplasty in patients with out-of-hospital cardiac arrest are controversial. Using data from the Parisian Region Out of hospital Cardiac ArresT prospective registry, we performed an analysis to assess the effect of an invasive strategy on hospital survival. Methods and Results— Between January 2003 and December 2008, 714 patients with out-of-hospital cardiac arrest were referred to a tertiary center in Paris, France. In 435 patients with no obvious extracardiac cause of arrest, an immediate coronary angiogram was performed at admission followed, if indicated, by coronary angioplasty. At least 1 significant coronary artery lesion was found in 304 (70%) patients, in 128 (96%) of 134 patients with ST-segment elevation on the ECG performed after the return of spontaneous circulation, and in 176 (58%) of 301 patients without ST-segment elevation. The hospital survival rate was 40%. Multivariable analysis showed successful coronary angioplasty to be an independent predictive factor of survival, regardless of the postresuscitation ECG pattern (odds ratio, 2.06; 95% CI, 1.16 to 3.66). Conclusions— Successful immediate coronary angioplasty is associated with improved hospital survival in patients with or without ST-segment elevation. Therefore, our findings support the use of immediate coronary angiography in patients with out-of-hospital cardiac arrest with no obvious noncardiac cause of arrest regardless of the ECG pattern.Background—Acute coronary occlusion is the leading cause of cardiac arrest. Because of limited data, the indications and timing of coronary angiography and angioplasty in patients with out-of-hospital cardiac arrest are controversial. Using data from the Parisian Region Out of hospital Cardiac ArresT prospective registry, we performed an analysis to assess the effect of an invasive strategy on hospital survival. Methods and Results—Between January 2003 and December 2008, 714 patients with out-of-hospital cardiac arrest were referred to a tertiary center in Paris, France. In 435 patients with no obvious extracardiac cause of arrest, an immediate coronary angiogram was performed at admission followed, if indicated, by coronary angioplasty. At least 1 significant coronary artery lesion was found in 304 (70%) patients, in 128 (96%) of 134 patients with ST-segment elevation on the ECG performed after the return of spontaneous circulation, and in 176 (58%) of 301 patients without ST-segment elevation. The hospital survival rate was 40%. Multivariable analysis showed successful coronary angioplasty to be an independent predictive factor of survival, regardless of the postresuscitation ECG pattern (odds ratio, 2.06; 95% CI, 1.16 to 3.66). Conclusions—Successful immediate coronary angioplasty is associated with improved hospital survival in patients with or without ST-segment elevation. Therefore, our findings support the use of immediate coronary angiography in patients with out-of-hospital cardiac arrest with no obvious noncardiac cause of arrest regardless of the ECG pattern.

Femoral vs Jugular Venous Catheterization and Risk of Nosocomial Events in Adults Requiring Acute Renal Replacement Therapy : A Randomized Controlled Trial

CONTEXT Based on concerns about the risk of infection, the jugular site is often preferred over the femoral site for short-term dialysis vascular access. OBJECTIVE To determine whether jugular catheterization decreases the risk of nosocomial complications compared with femoral catheterization. DESIGN, SETTING, AND PATIENTS A concealed, randomized, multicenter, evaluator-blinded, parallel-group trial (the Cathedia Study) of 750 patients from a network of 9 tertiary care university medical centers and 3 general hospitals in France conducted between May 2004 and May 2007. The severely ill, bed-bound adults had a body mass index (BMI) of less than 45 and required a first catheter insertion for renal replacement therapy. INTERVENTION Patients were randomized to receive jugular or femoral vein catheterization by operators experienced in placement at both sites. MAIN OUTCOME MEASURES Rates of infectious complications, defined as catheter colonization on removal (primary end point), and catheter-related bloodstream infection. RESULTS Patient and catheter characteristics, including duration of catheterization, were similar in both groups. More hematomas occurred in the jugular group than in the femoral group (13/366 patients [3.6%] vs 4/370 patients [1.1%], respectively; P = .03). The risk of catheter colonization at removal did not differ significantly between the femoral and jugular groups (incidence of 40.8 vs 35.7 per 1000 catheter-days; hazard ratio [HR], 0.85; 95% confidence interval [CI], 0.62-1.16; P = .31). A prespecified subgroup analysis demonstrated significant qualitative heterogeneity by BMI (P for the interaction term < .001). Jugular catheterization significantly increased incidence of catheter colonization vs femoral catheterization (45.4 vs 23.7 per 1000 catheter-days; HR, 2.10; 95% CI, 1.13-3.91; P = .017) in the lowest tercile (BMI <24.2), whereas jugular catheterization significantly decreased this incidence (24.5 vs 50.9 per 1000 catheter-days; HR, 0.40; 95% CI, 0.23-0.69; P < .001) in the highest tercile (BMI >28.4). The rate of catheter-related bloodstream infection was similar in both groups (2.3 vs 1.5 per 1000 catheter-days, respectively; P = .42). CONCLUSION Jugular venous catheterization access does not appear to reduce the risk of infection compared with femoral access, except among adults with a high BMI, and may have a higher risk of hematoma. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00277888.

platelet-activating factor receptor antagonist Bn 52021 in the treatment of severe sepsis: A randomized, double-blind, placebo-controlled, multicenter clinical trial

Objective: To evaluate the safety and efficacy of a natural platelet‐activating factor receptor antagonist, BN 52021 (Ginkgolide B), in the treatment of patients with sepsis syndrome. Design: Prospective, randomized, placebocontrolled, double‐blind, phase III, multicenter clinical trial. Setting: Twenty‐one academic medical center intensive care units in France. Patients: Two hundred sixty‐two patients with sepsis syndrome who received standard supportive care and antimicrobial therapy, in addition to the administration of platelet‐activating factor receptor antagonist or placebo. Interventions: Patients received either a 120‐mg dose of platelet‐activating factor receptor antagonist intravenously every 12 hrs over a 4‐day period or placebo. Main Outcome Measurements: All patients were evaluated for 28‐day, all‐cause mortality. Results: The 28‐day mortality rate was 51% for the placebo group and 42% for the platelet‐activating factor receptor antagonist group ( p = .17). However, the efficacy of platelet‐activating factor receptor antagonist was significantly greater in patients with Gram‐negative sepsis (test for interaction, p = .03). In a separate analysis of patients with and without Gram‐negative sepsis, the 28‐day mortality rate was 57% for the patients receiving placebo (30 deaths of 53 patients) and 33% for patients receiving platelet‐activating factor receptor antagonist (22 deaths of 67 patients; p = .01). Platelet‐activating factor receptor antagonist also significantly ( p = .01) reduced the mortality rate among patients with Gram‐negative sepsis who were in shock at entry into the study (mortality rate was 65% for placebo vs. 37% for platelet‐activating factor receptor antagonist) and among patients >60 yrs of age (mortality rate was 74% for placebo vs. 31% for platelet‐activating factor receptor antagonist). A Cox proportional‐hazards model identified five independent prognostic factors: a) adequacy of antibiotic therapy; b) severity of illness; c) renal failure; d) hematologic failure; and e) hepatic failure at study entry. When the Gram‐negative sepsis population was stratified by age and these five prognostic factors were controlled for, the relative risk of death of the platelet‐activating factor receptor antagonist group was 0.61 (0.34 to 1.08, 95% confidence interval; p = .09). This risk corresponds with an adjusted reduction in mortality rate of 39% for patients receiving plateletactivating factor receptor antagonist. No differences in mortality rates were found between the placebo and the platelet‐activating factor receptor antagonist groups in the absence of Gram‐negative sepsis. There were no differences in adverse events between the placebo and the treated groups. Conclusion: The studied platelet‐activating factor receptor antagonist (BN 52021) seems to be a safe and promising treatment for patients with severe Gram‐negative sepsis. (Crit Care Med 1994; 22:1720–1728)