Therapeutic vaccines for advanced non-small cell lung cancer.

BACKGROUND: New strategies in immunotherapy with specific antigens that trigger an anti-tumour immune response in people with lung cancer open the possibility of developing therapeutic vaccines aimed at boosting the adaptive immune response against cancer cells. OBJECTIVES: To evaluate the effectiveness and safety of different types of therapeutic vaccines for people with advanced non-small cell lung cancer. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, Wanfang Data, and China Journal Net (CNKI) up to 22 August 2023. SELECTION CRITERIA: We included parallel-group, randomised controlled trials evaluating a therapeutic cancer vaccine, alone or in combination with other treatments, in adults (> 18 years) with advanced non-small cell lung cancer (NSCLC), whatever the line of treatment. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Our primary outcomes were overall survival, progression-free survival, and serious adverse events; secondary outcomes were three- and five-year survival rates and health-related quality of life. MAIN RESULTS: We included 10 studies with 2177 participants. The outcome analyses included only 2045 participants (1401 men and 644 women). The certainty of the evidence varied by vaccine and outcome, and ranged from moderate to very low. We report only the results for primary outcomes here. TG4010 The addition of the vector-based vaccine, TG4010, to chemotherapy, compared with chemotherapy alone in first-line treatment, may result in little to no difference in overall survival (hazard ratio (HR) 0.83, 95% confidence interval (CI) 0.65 to 1.05; 2 studies, 370 participants; low-certainty evidence). It may increase progression-free survival slightly (HR 0.74, 95% CI 0.55 to 0.99; 1 study, 222 participants; low-certainty evidence). It may result in little to no difference in the proportion of participants with at least one serious treatment-related adverse event, but the evidence is very uncertain (risk ratio (RR) 0.70, 95% CI 0.23 to 2.19; 2 studies, 362 participants; very low-certainty evidence). Epidermal growth factor vaccine Epidermal growth factor vaccine, compared to best supportive care as switch maintenance treatment after first-line chemotherapy, may result in little to no difference in overall survival (HR 0.82, 95% CI 0.66 to 1.02; 1 study, 378 participants; low-certainty evidence), and in the proportion of participants with at least one serious treatment-related adverse event (RR 1.32, 95% CI 0.88 to 1.98; 2 studies, 458 participants; low-certainty evidence). hTERT (vx-001) The hTERT (vx-001) vaccine compared to placebo as maintenance treatment after first-line chemotherapy may result in little to no difference in overall survival (HR 0.97, 95% CI 0.70 to 1.34; 1 study, 190 participants). Racotumomab Racotumomab compared to placebo as a switch maintenance treatment post-chemotherapy was assessed in one study with 176 participants. It may increase overall survival (HR 0.63, 95% CI 0.46 to 0.87). It may make little to no difference in progression-free survival (HR 0.73, 95% CI 0.53 to 1.00) and in the proportion of people with at least one serious treatment-related adverse event (RR 1.03, 95% CI 0.15 to 7.18). Racotumomab versus docetaxel as switch maintenance therapy post-chemotherapy was assessed in one study with 145 participants. The study did not report hazard rates on overall survival or progression-free survival time, but the difference in median survival times was very small - less than one month. Racotumomab may result in little to no difference in the proportion of people with at least one serious treatment-related adverse event compared with docetaxel (RR 0.89, 95% CI 0.44 to 1.83). Personalised peptide vaccine Personalised peptide vaccine plus docetaxel compared to docetaxel plus placebo post-chemotherapy treatment may result in little to no difference in overall survival (HR 0.80, 95% CI 0.42 to 1.52) and progression-free survival (HR 0.78, 95% CI 0.43 to 1.42). OSE2101 The OSE2101 vaccine compared with chemotherapy, after chemotherapy or immunotherapy, was assessed in one study with 219 participants. It may result in little to no difference in overall survival (HR 0.86, 95% CI 0.62 to 1.19). It may result in a small difference in the proportion of people with at least one serious treatment-related adverse event (RR 0.95, 95% CI 0.91 to 0.99). SRL172 The SRL172 vaccine of killed Mycobacterium vaccae, added to chemotherapy, compared to chemotherapy alone, may result in no difference in overall survival, and may increase the proportion of people with at least one serious treatment-related adverse event (RR 2.07, 95% CI 1.76 to 2.43; 351 participants). AUTHORS' CONCLUSIONS: Adding a vaccine resulted in no differences in overall survival, except for racotumomab, which showed some improvement compared to placebo, but the difference in median survival time was very small (1.4 months) and the study only included 176 participants. Regarding progression-free survival, we observed no differences between the compared treatments, except for TG4010, which may increase progression-free survival slightly. There were no differences between the compared treatments in serious treatment-related adverse events, except for SRL172 (killed Mycobacterium vaccae) added to chemotherapy, which was associated with an increase in the proportion of participants with at least one serious treatment-related adverse event, and OSE2101, which may decrease slightly the proportion of people having at least one serious treatment-related adverse event. These conclusions should be interpreted cautiously, as the very low- to moderate-certainty evidence prevents drawing solid conclusions: many vaccines were evaluated in a single study with small numbers of participants and events.

Factors Influencing Occupational Stress Perceived by Emergency Nurses During Prehospital Care: A Systematic Review.

Objective: To assess personal and work-related factors influencing the stress levels of nurses during prehospital care. Specifically, to identify associations between the level of perceived stress, the degree of professional experience, and the level of knowledge. Secondly, to examine the relationship between stress levels and violence in the work environment. And third, to investigate the main protective factors against work-related stress during prehospital care. Methods: Systematic review in PubMed, WOS, Enfispo, Cochrane, and LILACS databases following the PRISMA methodology (last search 08/Aug/2023). Following the PECO framework, studies on occupational stress factors in ambulance emergency nurses were investigated. Studies in English or Spanish, from 2013 to 2023, and only research articles were admitted, thus excluding reviews, dissertations, and grey literature. Possible bias and level evidence were assessed using critical appraisal tools and GRADE. This protocol was registered in PROSPERO with code CRD42023446080. Results: Fourteen articles were selected, and n=855 prehospital nurses were identified. One study was a clinical trial, and the others were observational and qualitative. The level of evidence was very low (n=7), low (n=6), and moderate (n=1); any study was excluded due to methodological bias. Five categories of stressors were extracted: the management of the health service (ie, workload organisation, and resources), patient care (mainly paediatric care), interpersonal stressors (relationship with peers), environmental factors (exposure to injuries), and personal factors (training, experience, and coping strategies). Violence at work is frequent for prehospital nurses, implying both verbal and physical aggressions. Support from peers was associated with positive results against stress. Conclusion: Managing workload and improving resources in the work environment are essential to reduce fatigue and allow emotional processes to be addressed. Providing workers with coping skills also imposes on them the responsibility to cope with stress. Collective awareness is the main element in reducing the incidence of stress.

Understanding repertoire sequencing data through a multiscale computational model of the germinal center.

Sequencing of B-cell and T-cell immune receptor repertoires helps us to understand the adaptive immune response, although it only provides information about the clonotypes (lineages) and their frequencies and not about, for example, their affinity or antigen (Ag) specificity. To further characterize the identified clones, usually with special attention to the particularly abundant ones (dominant), additional time-consuming or expensive experiments are generally required. Here, we present an extension of a multiscale model of the germinal center (GC) that we previously developed to gain more insight in B-cell repertoires. We compare the extent that these simulated repertoires deviate from experimental repertoires established from single GCs, blood, or tissue. Our simulations show that there is a limited correlation between clonal abundance and affinity and that there is large affinity variability among same-ancestor (same-clone) subclones. Our simulations suggest that low-abundance clones and subclones, might also be of interest since they may have high affinity for the Ag. We show that the fraction of plasma cells (PCs) with high B-cell receptor (BcR) mRNA content in the GC does not significantly affect the number of dominant clones derived from single GCs by sequencing BcR mRNAs. Results from these simulations guide data interpretation and the design of follow-up experiments.

From affinity selection to kinetic selection in Germinal Centre modelling.

Affinity maturation is an evolutionary process by which the affinity of antibodies (Abs) against specific antigens (Ags) increases through rounds of B-cell proliferation, somatic hypermutation, and positive selection in germinal centres (GC). The positive selection of B cells depends on affinity, but the underlying mechanisms of affinity discrimination and affinity-based selection are not well understood. It has been suggested that selection in GC depends on both rapid binding of B-cell receptors (BcRs) to Ags which is kinetically favourable and tight binding of BcRs to Ags, which is thermodynamically favourable; however, it has not been shown whether a selection bias for kinetic properties is present in the GC. To investigate the GC selection bias towards rapid and tight binding, we developed an agent-based model of GC and compared the evolution of founder B cells with initially identical low affinities but with different association/dissociation rates for Ag presented by follicular dendritic cells in three Ag collection mechanisms. We compared an Ag collection mechanism based on association/dissociation rates of B-cell interaction with presented Ag, which includes a probabilistic rupture of bonds between the B-cell and Ag (Scenario-1) with a reference scenario based on an affinity-based Ag collection mechanism (Scenario-0). Simulations showed that the mechanism of Ag collection affects the GC dynamics and the GC outputs concerning fast/slow (un)binding of B cells to FDC-presented Ags. In particular, clones with lower dissociation rates outcompete clones with higher association rates in Scenario-1, while remaining B cells from clones with higher association rates reach higher affinities. Accordingly, plasma cell and memory B cell populations were biased towards B-cell clones with lower dissociation rates. Without such probabilistic ruptures during the Ag extraction process (Scenario-2), the selective advantage for clones with very low dissociation rates diminished, and the affinity maturation level of all clones decreased to the reference level.

Coupled Antigen and BLIMP1 Asymmetric Division With a Large Segregation Between Daughter Cells Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells and a DZ-to-LZ Ratio in the Germinal Center.

Memory B cells and antibody-secreting plasma cells are generated within germinal centers during affinity maturation in which B-cell proliferation, selection, differentiation, and self-renewal play important roles. The mechanisms behind memory B cell and plasma cell differentiation in germinal centers are not well understood. However, it has been suggested that cell fate is (partially) determined by asymmetric cell division, which involves the unequal distribution of cellular components to both daughter cells. To investigate what level and/or probability of asymmetric segregation of several fate determinant molecules, such as the antigen and transcription factors (BCL6, IRF4, and BLIMP1) recapitulates the temporal switch and DZ-to-LZ ratio in the germinal center, we implemented a multiscale model that combines a core gene regulatory network for plasma cell differentiation with a model describing the cellular interactions and dynamics in the germinal center. Our simulations show that BLIMP1 driven plasma cell differentiation together with coupled asymmetric division of antigen and BLIMP1 with a large segregation between the daughter cells results in a germinal center DZ-to-LZ ratio and a temporal switch from memory B cells to plasma cells that have been observed in experiments.

Mild AST elevation as an early sign of COVID-19 severity in a multicenter Madrid cohort.

INTRODUCTION: liver enzyme elevation has been reported in SARS-CoV-2 disease (COVID-19) in heterogeneous cohorts, mainly from China. Comprehensive reports from other countries are needed. In this study, we dissect the pattern, evolution, and predictive value of such abnormalities in a cohort from Madrid, Spain. METHODS: a retrospective study with a prospective 14-day follow-up of 373 patients with confirmed COVID-19 in five Madrid hospitals, including 50 outpatients. A COVID-19 severe course was defined as the need for mechanical ventilation. RESULTS: a total of 33.1 % of hospitalized patients showed baseline AST elevation and 28.5 % showed ALT elevation, compared with 12 % and 8 % of outpatients (p ≤ 0.001). Baseline AST, ALT and GGT levels correlated with LDH and C-reactive protein (CRP) levels (r ≤ 0.598, p < 0.005). AST elevation was associated with other severity markers such as male sex, lymphopenia, and pneumonia on X-Ray (p < 0.05 for all). ALP and bilirubin levels were rarely increased. Patients with elevated baseline AST showed a progressive normalization of this enzyme and an increase in ALT and GGT levels. Patients with normal baseline AST showed a flattened evolution pattern with levels within the range. Patients with a severe course of COVID-19 more frequently showed elevated baseline AST than those with a milder evolution (54.2 % vs. 25.4 %, p < 0.001). Age, AST and CRP were independent risk factors for a severe course of COVID-19. CONCLUSION: mild liver enzyme elevation is associated with COVID-19 severity. Baseline AST is an independent predictor of severe COVID-19 course, and tends to normalize over time. ALT and GGT show a late elevation.

[Palliative Sedation at the End of Life: A Comparative Study of Chronic Obstructive Pulmonary Disease and Lung Cancer Patients].

BACKGROUND: Although patients with chronic obstructive pulmonary disease (COPD) receive poor-quality palliative care, information about the use of palliative sedation (PS) in the last days of life is very scarce. OBJECTIVES: To compare the use of PS in hospitalized patients who died from COPD or lung cancer and identify factors correlating with PS application. METHODS: In a retrospective observational cohort study, from 1,675 patients died at a teaching hospital between 2013 and 2015, 109 patients who died from COPD and 85 from lung cancer were compared. Sociodemographic data, clinical characteristics, health care resource utilization, application of PS and prescribed drugs were recorded. RESULTS: In the last 6 months of life, patients who died from COPD had more hospital admissions due to respiratory causes and less frequent support by a palliative home care team (PHCT). Meanwhile, during their last hospitalization, patients who died from COPD had fewer do-not-resuscitate orders and were subjected to more intensive care unit admissions and cardiopulmonary resuscitation maneuvers. PS was applied less frequently in patients who died from COPD than in those who died from lung cancer (31 vs. 53%, p = 0.002). Overall, previous use of opioid drugs, support by a PHCT, and a diagnosis of COPD (adjusted odds ratio 0.48, 95% CI: 0.26-0.89, p = 0.020) were retained as factors independently related to PS. In COPD patients, only previous use of opioid drugs was identified as a PS-related factor. CONCLUSION: During their last days of life, hospitalized COPD patients receive PS less frequently than patients with lung cancer.

Hospital Readmissions of Discharged Patients with COVID-19.

OBJECTIVE: To analyse the rate of occurrence and the clinical variables associated with readmission of patients who had previously been discharged after admission for COVID-19. SETTING: University hospital in Madrid (Spain). PARTICIPANTS: Sixty-one patients (74% male) who presented COVID-19 were readmitted during the 3 weeks after discharge from hospital. INTERVENTIONS: Nested case-control study paired (1:1 ratio) by age, sex and period of admission. OUTCOME MEASURES: Rate of readmission rate of patients discharged after suffering COVID-19 and identification of the clinical variables associated with it. RESULTS: Out of 1368 patients who were discharged during the study period, 61 patients (4.4%) were readmitted. Immunocompromised patients (N=10.2%) were at increased risk for readmission (p=0.04). There was also a trend towards a higher probability of readmission in hypertensive patients (p=0.07). Cases had had a shorter hospital stay and a higher prevalence of fever during the 48 hours prior to discharge. There were no significant differences in oxygen levels measured at admission and discharge by pulse oximetry intra-subject or between the groups. Neutrophil-to-lymphocyte ratio at hospital admission tended to be higher in cases than in controls (p=0.06). Neither glucocorticoids nor anticoagulants prescribed at hospital discharge were associated with a lower readmission rate. Patients who were readmitted due to a thrombotic event (8 patients, 13.1%) presented a higher level of D-dimer at discharge of initial admission. CONCLUSION: The rate of readmission after discharge from hospital for COVID-19 was low. Immunocompromised patients and those presenting with fever during the 48 hours prior to discharge were at greater risk of readmission to hospital.

Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help.

Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.

Static lung hyperinflation is an independent risk factor for lung cancer in patients with chronic obstructive pulmonary disease.

INTRODUCTION: Static hyperinflation, a hallmark characteristic of some patients with chronic obstructive pulmonary disease, is related to higher mortality and cardiovascular morbidity. However, information about its association with lung cancer is scarce. Our aim was to evaluate whether static hyperinflation is associated with future risk of lung cancer in COPD patients. METHODS: A cohort of 848 COPD patients recruited outside the hospital setting was monitored for an average period of 4.3 years, totaling 2858 person-years, regarding diagnosis of cancer of any origin or lung cancer. Static hyperinflation was defined by functional residual capacity measured by plethysmography greater than 120% of the predicted value. RESULTS: The incidence rates for cancer of any origin and lung cancer were 16.0 (95%CI, 15.1-17.8) and 8.7 (95%CI, 7.7-9.8) per 1000 patient-years, respectively. Among the patients with lung cancer, non-small cell lung cancer predominated (88%). In a stepwise multivariate Cox regression model, body mass index (BMI), pack-years, Charlson index, and postbronchodilator FEV1/FVC ratio were retained as independent predictors of cancer of any origin. In contrast, features associated with a future risk of lung cancer included older age, low BMI, increased pack-years and presence of static hyperinflation (adjusted hazard ratio: 4.617, 95%CI: 1.007-21.172, p = 0.049). CONCLUSION: In a general COPD outpatient population, static hyperinflation is an independent risk factor for the development of lung cancer, which might contribute towards justifying the excess mortality identified in COPD patients with hyperinflation.

Classification of Airflow Limitation Based on z-Score Underestimates Mortality in Patients with Chronic Obstructive Pulmonary Disease.

RATIONALE: Global Lung Function Initiative recommends reporting lung function measures as z-score, and a classification of airflow limitation (AL) based on this parameter has recently been proposed. OBJECTIVES: To evaluate the prognostic capacity of the AL classifications based on z-score or percentage predicted of FEV1 in patients with chronic obstructive pulmonary disease (COPD). METHODS: A cohort of 2,614 patients with COPD recruited outside the hospital setting was examined after a mean (± SD) of 57 ± 13 months of follow-up, totaling 10,322 person-years. All-cause mortality was analyzed, evaluating the predictive capacity of several AL staging systems. MEASUREMENTS AND MAIN RESULTS: Based on Global Initiative for Chronic Obstructive Lung Disease guidelines, 461 patients (17.6%) had mild, 1,452 (55.5%) moderate, 590 (22.6%) severe, and 111 (4.2%) very severe AL. According to z-score classification, 66.3% of patients remained with the same severity, whereas 23.7% worsened and 10.0% improved. Unlike other staging systems, patients with severe AL according to z-score had higher mortality than those with very severe AL (increase of risk by 5.2 and 3.9 times compared with mild AL, respectively). The predictive capacity for 5-year survival was slightly higher for FEV1 expressed as percentage of predicted than as z-score (area under the curve: 0.714-0.760 vs. 0.649-0.708, respectively). A severity-dependent relationship between AL grades by z-score and mortality was only detected in patients younger than age 60 years. CONCLUSIONS: In patients with COPD, the AL classification based on z-score predicts worse mortality than those based on percentage of predicted. It is possible that the z-score underestimates AL severity in patients older than 60 years of age with severe functional impairment.

Prognostic Value of the Six-Second Spirometry in Patients with Chronic Obstructive Pulmonary Disease: A Cohort Study.

BACKGROUND: The six-second spirometry has been proposed as an alternative to diagnose airflow limitation, although its prognostic value in patients with chronic obstructive pulmonary disease (COPD) remains unknown. The purpose of this study was to determine the prognostic value of the postbronchodilator forced expiratory volume in 1 second (FEV1)/forced expiratory volume in 6 seconds (FEV6) ratio and FEV6 in COPD patients. METHODS AND FINDINGS: The study population consisted of 2,614 consecutive stable patients with COPD. The patients were monitored for an average period of 4.3 years regarding mortality, hospitalizations by COPD exacerbations, diagnosis of lung cancer, and annual lung function decline. The overall rate of death was 10.7 (95%CI: 8.7-12.7) per 1000 person-years. In addition to male gender, age and comorbidity, FEV6 (hazard ratio [HR]: 0.981, 95%CI: 0.968-0.003) and FEV1/FEV6 quartiles (lowest quartile (<74% pred.): HR 3.558, 95%CI: 1.752-7.224; and second quartile (74-84% pred.): HR 2.599, 95%CI: 1.215-5.561; versus best quartile (>0.89% pred.)) were independently associated with mortality, whereas FEV1 was not retained in the model. 809 patients (30.9%) had at least one hospital admission due to COPD exacerbation. In addition to sex, age, smoking and comorbidity, FEV1 and FEV1/FEV6 quartiles were independent risk factors of hospitalization. FEV6 was the only spirometric parameter independently related with lung function annual decline, while the FEV6 and FEV1/FEV6 quartiles were independent risk factors for lung cancer. CONCLUSIONS: In a general COPD outpatient population, airflow obstruction assessed by the FEV1/FEV6 is an independent risk factor for both death and hospitalization.