Aberrant Lck Signal via CD28 Costimulation Augments Antigen-Specific Functionality and Tumor Control by Redirected T Cells with PD-1 Blockade in Humanized Mice.

Purpose: Combination therapy of adoptively transferred redirected T cells and checkpoint inhibitors aims for higher response rates in tumors poorly responsive to immunotherapy like malignant pleural mesothelioma (MPM). Only most recently the issue of an optimally active chimeric antigen receptor (CAR) and the combination with checkpoint inhibitors is starting to be addressed.Experimental Design: Fibroblast activation protein (FAP)-specific CARs with different costimulatory domains, including CD28, Δ-CD28 (lacking lck binding moiety), or 4-1BB were established. CAR-T cells were characterized in vitro and antitumor efficacy was tested in vivo in a humanized mouse model in combination with PD-1 blockade. Finally, the Δ-CD28 CAR was tested clinically in a patient with MPM.Results: All the three CARs demonstrated FAP-specific functionality in vitro Gene expression data indicated a distinct activity profile for the Δ-CD28 CAR, including higher expression of genes involved in cell division, glycolysis, fatty acid oxidation, and oxidative phosphorylation. In vivo, only T cells expressing the Δ-CD28 CAR in combination with PD-1 blockade controlled tumor growth. When injected into the pleural effusion of a patient with MPM, the Δ-CD28 CAR could be detected for up to 21 days and showed functionality.Conclusions: Overall, anti-FAP-Δ-CD28/CD3ζ CAR T cells revealed superior in vitro functionality, better tumor control in combination with PD-1 blockade in humanized mice, and persistence up to 21 days in a patient with MPM. Therefore, further clinical investigation of this optimized CAR is warranted. Clin Cancer Res; 24(16); 3981-93. ©2018 AACR.

Resuscitation with polymeric plasma substitutes is permissive for systemic inflammatory response syndrome and sepsis in multiply injured patients: a retrospective cohort study.

OBJECTIVE: Multiple trauma is often accompanied by systemic inflammatory response syndrome (SIRS). The aim of this study was to investigate the impact of polymeric plasma substitutes on the development of SIRS or sepsis. METHODS: We included 2969 patients aged ≥16 years with an Injury Severity Score (ISS) >16 in this study. The sample was subdivided into three groups: patients who did not receive colloids and those who received <5L colloids and >5L colloids within the first 48 h. Data were analyzed using IBM SPSS® for Windows version 22.0; analysis of variance was used for continuous normally distributed data and Kruskal-Wallis test for categorical data. The predictive quality of colloid treatment was analyzed using the receiver operating characteristic (ROC) curves. Independent predictively was analyzed by binary logistic regression. Data were considered significant if P < 0.05. Data are presented as the mean ± standard deviation. RESULTS: The SIRS score increased with the amount of colloid used (1.9 ± 1.4 vs. 2.4 ± 1.2 vs. 3.2 ± 0.9; P < 0.001). However, the predictive quality was low, with an area under the ROC of 0.693 for SIRS and 0.669 for sepsis (P < 0.001). Binary logistic regression revealed colloids as an independent factor for the development of SIRS and sepsis (odds ratios: SIRS 3.325 and sepsis 8.984; P < 0.001). CONCLUSION: Besides other factors, colloids have a significant permissive effect and are independent predictors for the development of SIRS and sepsis in multiply injured patients. Trial registration 'Retrospektive Analysen in der Chirurgischen Intensivmedizin' No. St. V. 01-2008.

C-MAC videolaryngoscope compared with direct laryngoscopy for rapid sequence intubation in an emergency department: A randomised clinical trial.

BACKGROUND: Airway management in the emergency room can be challenging when patients suffer from life-threatening conditions. Mental stress, ignorance of the patient's medical history, potential cervical injury or immobilisation and the presence of vomit and/or blood may also contribute to a difficult airway. Videolaryngoscopes have been introduced into clinical practice to visualise the airway and ultimately increase the success rate of airway management. OBJECTIVE: The aim of this study was to test the hypothesis that the C-MAC videolaryngoscope improves first-attempt intubation success rate compared with direct laryngoscopy in patients undergoing emergency rapid sequence intubation in the emergency room setting. DESIGN: A randomised clinical trial. SETTING: Emergency Department of the University Hospital, Zurich, Switzerland. PATIENTS: With approval of the local ethics committee, we prospectively enrolled 150 patients between 18 and 99 years of age requiring emergency rapid sequence intubation in the emergency room of the University Hospital Zurich. Patients were randomised (1 : 1) to undergo tracheal intubation using the C-MAC videolaryngoscope or by direct laryngoscopy. INTERVENTIONS: Owing to ethical considerations, patients who had sustained maxillo-facial trauma, immobilised cervical spine, known difficult airway or ongoing cardiopulmonary resuscitation were excluded from our study. All intubations were performed by one of three very experienced anaesthesia consultants. MAIN OUTCOME MEASURES: First-attempt success rate served as our primary outcome parameter. Secondary outcome parameters were time to intubation; total number of intubation attempts; Cormack and Lehane score; inadvertent oesophageal intubation; ease of intubation; complications including violations of the teeth, injury/bleeding of the larynx/pharynx and aspiration/regurgitation of gastric contents; necessity of using further alternative airway devices for successful intubation; maximum decrease of oxygen saturation and technical problems with the device. RESULTS: A total of 150 patients were enrolled, but three patients had to be excluded from the analysis, resulting in 74 patients in the C-MAC videolaryngoscopy group and 73 patients in the direct laryngoscopy group. Tracheal intubation was achieved successfully at the first attempt in 73 of 74 patients in the C-MAC group and all patients in the direct laryngoscopy group (P = 1.0). Time to intubation was similar (32 ±â€Š11 vs. 31 ±â€Š9 s, P = 0.51) in both groups. Visualisation of the vocal cords, represented as the Cormack and Lehane score, was significantly better using the C-MAC videolaryngoscope (P < 0.001). CONCLUSION: Our study demonstrates that visualisation of the vocal cords was improved by using the C-MAC videolaryngoscope compared with direct laryngoscopy. Better visualisation did not improve first-attempt success rate, which in turn was probably based on the high level of experience of the participating anaesthesia consultants. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT02297113.

Advanced airway management in an anaesthesiologist-staffed Helicopter Emergency Medical Service (HEMS): A retrospective analysis of 1047 out-of-hospital intubations.

INTRODUCTION: Airway management in the out-of-hospital emergency setting is challenging. Failed and even prolonged airway management is associated with serious clinical consequences, such as desaturation, bradycardia, airway injuries, or aspiration. The overall success rate of tracheal intubation ranges between 77% and 99%, depending on the level of experience of the provider. Therefore, advanced airway management should only be performed by highly-skilled and experienced providers. METHODS: 9765 patients were treated in the out-of-hospital emergency setting by the anaesthesiologist-staffed Helicopter Emergency Medical Services (HEMS) between 2002 and 2014. Patients successfully intubated upon the first attempt were compared to patients who required more than one intubation attempts regarding several potential confounding factors such as age, gender, on-going CPR, NACA Score, initial GCS, prior administration of anaesthetic drugs, neuromuscular blocking agents, and vasopressors. RESULTS: 1573 out of 9765 patients (16.1%) required advanced airway management. 459 patients had already been intubated upon arrival of the HEMS, whereas 1114 patients (11.4%) underwent advanced airway management by the HEMS physician. 67 patients had to be excluded. Data for the remaining 1047 patients (790 males and 257 females) were analyzed further. Primary use of an alternative airway device was reported in 59 patients (5.6%), whereas 988 patients (94.4%) underwent laryngoscopy-guided tracheal intubation. 952 patients (96.4%) could be intubated upon the first attempt and overall intubation success was 99.5% (983 out of 988). CONCLUSION: Our study demonstrates that HEMS physicians performed airway management frequently and that both the first attempt as well as the overall success rate of tracheal intubation was high. Together with the fact that all failed and difficult intubations were successfully recognized and handled and that no surgical airway had to be established, the current study once more underlines the importance of proper training of HEMS care providers regarding airway management.

Sex and Age Aspects in Patients Suffering From Out-Of-Hospital Cardiac Arrest: A Retrospective Analysis of 760 Consecutive Patients.

Cardiopulmonary resuscitation (CPR) is indicated in patients suffering from out-of-hospital cardiac arrest. Several studies suggest a sex- and age-based bias in the treatment of these patients. This particular bias may have a significant impact on the patient's outcome. However, the reasons for these findings are still unclear and discussed controversially. Therefore, the aim of this study was to retrospectively analyze treatment and out-of-hospital survival rates for potential sex- and age-based differences in patients requiring out-of-hospital CPR provided by an emergency physician in the city of Zurich, Switzerland.A total of 3961 consecutive patients (2003-2009) were included in this retrospective analysis to determine the frequency of out-of-hospital CPR and prehospital survival rate, and to identify potential sex- and age-based differences regarding survival and treatment of the patients.Seven hundred fifty-seven patients required CPR during the study period. Seventeen patients had to be excluded because of incomplete or inconclusive documentation, resulting in 743 patients (511 males, 229 females) undergoing further statistical analysis. Female patients were significantly older, compared with male patients (68 ±â€Š18 [mean ±â€ŠSD] vs 64 ±â€Š18 years, P = .012). Men were resuscitated slightly more often than women (86.4% vs 82.1%). Overall out-of-hospital mortality rate was found to be 81.2% (492/632 patients) with no differences between sexes (82.1% for males vs 79% for females, odds ratio 1.039, 95% confidence interval 0.961-1.123). No sex differences were detected in out-of-hospital treatment, as assessed by the different medications administered, initial prehospital Glasgow Coma Scale, and prehospital suspected leading diagnosis.The data of our study demonstrate that there was no sex-based bias in treating patients requiring CPR in the prehospital setting in our physician-led emergency ambulance service.

The C-MAC videolaryngoscope compared with conventional laryngoscopy for rapid sequence intubation at the emergency department: study protocol.

BACKGROUND: Especially in the emergency setting, rapid and successful airway management is of major importance. Conventional endotracheal intubation is challenging and requires high level of individual skills and experience. Videolaryngoscopes like the C-MAC are likely to offer better glottis visualization and serve as alternatives to conventional endotracheal intubation. The aim of this study is to compare clinical performance and feasibility of the C-MAC videolaryngoscope compared to conventional endotracheal intubation in the emergency setting. METHODS/DESIGN: This study is designed as a prospective, patient-blinded, mono-center, randomized cohort study. This study will be performed at the Emergency Department of the University Hospital Zurich, Zurich, Switzerland. All patients transferred to the Emergency Department and requiring emergent endotracheal intubation will be screened. Successful intubation with first intubation attempt will serve as the primary outcome. Time to intubation, intubation attempts, Cormack & Lehane Score, ease of intubation, complications, necessity of using alternate intubation device, maximum drop of saturation, and potential technical problems serve as secondary outcomes. DISCUSSION: In the clinical setting, the ultimate success rate of endotracheal intubation ranges between 97% and 99%. Unexpected difficulties during laryngoscopy and poor glottis visualization occur in up to 9% of all cases. In these cases, videolaryngoscopes may increase success rate of initial intubation attempt and thereby patient safety. TRIAL REGISTRATION: www.clinicaltrials.gov (identifier NCT02297113 ).

Incidence of difficult airway situations during prehospital airway management by emergency physicians--a retrospective analysis of 692 consecutive patients.

INTRODUCTION: In the prehospital setting, advanced airway management is challenging as it is frequently affected by facial trauma, pharyngeal obstruction or limited access to the patient and/or the patient's airway. Therefore, incidence of prehospital difficult airway management is likely to be higher compared to the in-hospital setting and success rates of advanced airway management range between 80 and 99%. METHODS: 3961 patients treated by an emergency physician in Zurich, Switzerland were included in this retrospective analysis in order to determine the incidence of a difficult airway along with potential circumstantial risk factors like gender, necessity of CPR, NACA score, GCS, use and type of muscle relaxant and use of hypnotic drugs. RESULTS: 692 patients underwent advanced prehospital airway management. Seven patients were excluded due to incomplete or incongruent documentation, resulting in 685 patients included in the statistical analysis. Difficult intubation was recorded in 22 patients, representing an incidence of a difficult airway of 3.2%. Of these 22 patients, 15 patients were intubated successfully, whereas seven patients (1%) had to be ventilated with a bag valve mask during the whole procedure. CONCLUSION: In this physician-led service one out of five prehospital patients requires airway management. Incidence of advanced prehospital difficult airway management is 3.2% and eventual success rate is 99%, if performed by trained emergency physicians. A total of 1% of all prehospital intubation attempts failed and alternative airway device was necessary.