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BACKGROUND: Pembrolizumab has a manageable safety profile as described in its label, which was primarily based on 2799 patients who participated in clinical trials for melanoma or non-small cell lung cancer. Here, we evaluated the safety of pembrolizumab in a broader population of patients from 31 advanced cancer clinical trials across 19 cancer types. METHODS: Safety was analyzed in patients who received at least one dose of pembrolizumab (200 mg every 3 weeks [Q3W], 10 mg/kg Q2W or Q3W, or 2 mg/kg Q3W). Adverse events (AEs) and immune-mediated AEs and infusion reactions were evaluated. RESULTS: Safety data from 8937 patients in 31 trials of pembrolizumab monotherapy were pooled (median, seven administrations; range, 1-59). Median duration on treatment was 4.1 months (range, 0.03-40.1). AEs occurred in 96.6% of patients. Grade 3-5 AEs occurred in 50.6% of patients. AEs led to pembrolizumab discontinuation in 12.7% of patients and death in 5.9%. Immune-mediated AEs and infusion reactions occurred in 23.7% of patients (4.6% experienced multiple immune-mediated AEs/infusion reactions) and led to pembrolizumab discontinuation in 3.6% and death in 0.2%. Grade 3-5 immune-mediated AEs occurred in 6.3% of patients. Serious immune-mediated AEs and infusion reactions occurred in 6.0% of patients. Median time to immune-mediated AE onset was 85 days (range, 13-163). Of 2657 immune-mediated AEs, 22.3% were initially treated with prednisone ≥ 40 mg/day or equivalent, and 8.3% were initially treated with lower steroid doses. CONCLUSIONS: This pooled analysis of 31 clinical trials showed that pembrolizumab has a consistent safety profile across indications.

In patients with locally advanced cancer without distant metastases, the neoadjuvant setting presents a platform to evaluate new drugs. For mismatch repair proficient/microsatellite stable (pMMR/MSS) colon and rectal cancer, immunotherapy has shown limited efficacy. Herein, we report exceptional responses observed with neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti-CTLA-4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in two patients with pMMR/MSS colon and rectal cancer. The histological pattern of rapid immune response observed (inside-out (serosa-to-mucosa) tumor regression) has not been described previously in this setting. Spatial biology analyses (RareCyte Inc.) reveal mechanisms of actions of BOT, a novel innate-adaptive immune activator. These observations have downstream implications for clinical trial designs using neoadjuvant immunotherapy and potentially sparing patients chemotherapy.

ObjectivesWe aimed to describe emergency department (ED) care transition interventions delivered to older adults with cognitive impairment, identify relevant patient-centered outcomes, and determine priority research areas for future investigation.DesignSystematic scoping review.Setting and participantsED patients with cognitive impairment and/or their care partners.MethodsInformed by the clinical questions, we conducted systematic electronic searches of medical research databases for relevant publications following published guidelines. The results were presented to a stakeholder group representing ED-based and non-ED-based clinicians, individuals living with cognitive impairment, care partners, and advocacy organizations. After discussion, they voted on potential research areas to prioritize for future investigations.ResultsFrom 3848 publications identified, 78 eligible studies underwent full text review, and 10 articles were abstracted. Common ED-to-community care transition interventions for older adults with cognitive impairment included interdisciplinary geriatric assessments, home visits from medical personnel, and telephone follow-ups. Intervention effects were mixed, with improvements observed in 30-day ED revisit rates but most largely ineffective at promoting connections to outpatient care or improving secondary outcomes such as physical function. Outcomes identified as important to adults with cognitive impairment and their care partners included care coordination between providers and inclusion of care partners in care management within the ED setting. The highest priority research area for future investigation identified by stakeholders was identifying strategies to tailor ED-to-community care transitions for adults living with cognitive impairment complicated by other vulnerabilities such as social isolation or economic disadvantage.Conclusions and implicationsThis scoping review identified key gaps in ED-to-community care transition interventions delivered to older adults with cognitive impairment. Combined with a stakeholder assessment and prioritization, it identified relevant patient-centered outcomes and clarifies priority areas for future investigation to improve ED care for individuals with impaired cognition, an area of critical need given the current population trends.

Background and Objectives: Prehospital Advanced Life Support (ALS) is important to improve patient outcomes in children with seizures, yet data is limited regarding national prehospital variation in ALS response for these children. We aimed to determine the variation in ALS response and prehospital administration of antiepileptic medication for children with seizures across the United States.Methods: We analyzed children

OBJECTIVES: To identify research and practice gaps to establish future research priorities to advance the detection of cognitive impairment and dementia in the emergency department (ED). DESIGN: Literature review and consensus-based rankings by a transdisciplinary, stakeholder task force of experts, persons living with dementia, and care partners. SETTING AND PARTICIPANTS: Scoping reviews focused on adult ED patients. METHODS: Two systematic scoping reviews of 7 medical research databases focusing on best tools and approaches for detecting cognitive impairment and dementia in the ED in terms of (1) most accurate and (2) most pragmatic to implement. The results were screened, reviewed, and abstracted for relevant information and presented at the stakeholder consensus conference for discussion and ranked prioritization. RESULTS: We identified a total of 1464 publications and included 45 to review for accurate tools and approaches for detecting cognitive impairment and dementia. Twenty-seven different assessments and instruments have been studied in the ED setting to evaluate cognitive impairment and dementia, with many focusing on sensitivity and specificity of instruments to screen for cognitive impairment. For pragmatic tools, we identified a total of 2166 publications and included 66 in the review. Most extensively studied tools included the Ottawa 3DY and Six-Item Screener (SIS). The SIS was the shortest to administer (1 minute). Instruments with the highest negative predictive value were the SIS (vs MMSE) and the 4 As Test (vs expert diagnosis). The GEAR 2.0 Advancing Dementia Care Consensus conference ranked research priorities that included the need for more approaches to recognize more effectively and efficiently persons who may be at risk for cognitive impairment and dementia, while balancing the importance of equitable screening, purpose, and consequences of differentiating various forms of cognitive impairment. CONCLUSIONS AND IMPLICATIONS: The scoping review and consensus process identified gaps in clinical care that should be prioritized for research efforts to detect cognitive impairment and dementia in the ED setting. These gaps will be addressed as future GEAR 2.0 research funding priorities.

OBJECTIVES: To synthesize published research exploring emergency department (ED) communication strategies and decision-making with persons living with dementia (PLWD) and their care partners as the basis for a multistakeholder consensus conference to prioritize future research. DESIGN: Systematic scoping review. SETTINGS AND PARTICIPANTS: PLWD and their care partners in the ED setting. METHODS: Informed by 2 Patient-Intervention-Comparison-Outcome (PICO) questions, we conducted systematic electronic searches of medical research databases for relevant publications following standardized methodological guidelines. The results were presented to interdisciplinary stakeholders, including dementia researchers, clinicians, PLWD, care partners, and advocacy organizations. The PICO questions included: How does communication differ for PLWD compared with persons without dementia? Are there specific communication strategies that improve the outcomes of ED care? Future research areas were prioritized. RESULTS: From 5451 studies identified for PICO-1, 21 were abstracted. From 2687 studies identified for PICO-2, 3 were abstracted. None of the included studies directly evaluated communication differences between PLWD and other populations, nor the effectiveness of specific communication strategies. General themes emerging from the scoping review included perceptions by PLWD/care partners of rushed ED communication, often exacerbated by inconsistent messages between providers. Care partners consistently reported limited engagement in medical decision-making. In order, the research priorities identified included: (1) Barriers/facilitators of effective communication; (2) valid outcome measures of effective communication; (3) best practices for care partner engagement; (4) defining how individual-, provider-, and system-level factors influence communication; and (5) understanding how each member of ED team can ensure high-quality communication. CONCLUSIONS AND IMPLICATIONS: Research exploring ED communication with PLWD is sparse and does not directly evaluate specific communication strategies. Defining barriers and facilitators of effective communication was the highest-ranked research priority, followed by validating outcome measures associated with improved information exchange.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

Matrix metalloproteinase-9 (MMP9) selectively cleaves extracellular matrix proteins contributing to tumor growth and an immunosuppressive microenvironment. This study evaluated andecaliximab (ADX), an inhibitor of MMP9, in combination with nivolumab (NIVO), for the treatment of advanced gastric cancer. Phase 2, open-label, randomized multicenter study evaluating the efficacy, safety, and pharmacodynamics of ADX+NIVO versus NIVO in patients with pretreated metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and adverse events (AEs). We explored the correlation of efficacy outcomes with biomarkers. 144 patients were randomized; 141 were treated: 81% white, 69% male, median age was 61 years in the ADX+NIVO group and 62 years in the NIVO-alone group. The ORR was 10% (95% CI 4 to 19) in the ADX+NIVO group and 7% (95% CI 2 to 16) in the NIVO-alone group (OR: 1.5 (95% CI 0.4 to 6.1; p=0.8)). There was no response or survival benefit associated with adding ADX. AE rates were comparable in both treatment groups; the most common AEs were fatigue, decreased appetite, nausea, and vomiting. Programmed cell death ligand 1, interferon-γ (IFN), and intratumoral CD8+ cell density were not associated with treatment response or survival. The gene signature most correlated with shorter survival was the epithelial-to-mesenchymal gene signature; high transforming growth factor (TGF)-β fibrosis score was negatively associated with OS (p=0.036). Gene expression analysis of baseline tumors comparing long-(1+ years) and short-term (

BackgroundPlatinum and fluoropyrimidine combinations typically comprise first-line (1L) therapy in advanced gastric cancer or gastroesophageal junction adenocarcinoma (G/GEA), although controversy exists regarding the use of 5doublet versus triplet cytotoxic regimens. Historically, second-line (2L) and third-line or later (3L+) therapy has been fragmented. Recent trials have increased the need for optimal treatment sequencing in advanced G/GEA.Materials and methodsWe conducted a systematic search of peer-reviewed manuscripts of randomized clinical trials examining 1L, 2L, and 3L+ therapy for advanced G/GEA published from 2009 through November 19, 2019. When available, overall survival, progression-free survival, time to progression, overall response rate, and toxicity were extracted from each and compared descriptively.ResultsIn 1L therapy, chemotherapy triplets demonstrated variable efficacy improvements with invariable increased toxicity compared with platinum/fluoropyrimidine doublets. Currently, the only published report of positive outcomes using biologics in 1L describes adding trastuzumab in HER2-overexpressing advanced G/GEA. In 2L, doublet chemotherapy regimens are not uniformly more efficacious than single-agent taxanes or irinotecan, and ramucirumab has demonstrated improved outcomes both as monotherapy and in combination.ConclusionFor advanced G/GEA, review of trial results from 2009-2019 support 1L therapy with platinum and fluoropyrimidine and sequencing with taxanes or irinotecan in combination with biologics as effective 2L options. Escalating to a triplet may add some efficacy at the expense of added toxicity.Implications for practiceThe rapidly changing treatment landscape for advanced gastric cancer includes increasing options for refractory disease. With multiple first-line platinum-based regimens, identification of those with the best benefit-to-risk ratio may provide guidance on treatment sequencing strategies. This article presents findings from the published literature of randomized controlled trials that included a first-line platinum/fluoropyrimidine combination and, for second-line trials, patients with platinum/fluoropyrimidine-refractory disease. This guiding summary could be a tool for clinicians to identify the optimal first-line regimen(s) followed by a strategy for subsequent regimens.

AUDIENCE: This simulation-based training focuses on the most common and high risk pediatric prehospital scenarios in low- and middle-income countries (LMIC). The curriculum was developed based on a needs assessment to train Ministry of Health and Wellness (MOHW) prehospital providers in Botswana specifically for pediatric resuscitation and could be used for emergency medical services (EMS) providers in other LMIC. After participating in this curriculum, providers should enhance their assessment and interventions in acutely ill pediatric prehospital patients. LENGTH OF CURRICULUM: The entire course was designed to be presented over two days with 6-8 hours of instruction each day. INTRODUCTION: In recent years, prehospital medicine has shown continued growth in LMICs, specifically in Sub-Saharan Africa. As these programs develop focused training for the pediatric population, equipping the workforce with pediatric resuscitation skills is essential. A few years after its inception, the Botswana MOHW identified deficiencies in their current training program and sought external expertise and educational training. We partnered with the MOHW to create and implement a novel, prehospital simulation curriculum to teach pediatric resuscitation to prehospital providers. Our aim was to create a curriculum based on the needs of the community that could also be implemented in other similar resource-limited settings. This course included didactic sessions, five simulation scenarios using low fidelity mannequins and three pediatric-focused skill sessions. This program was found to be effective based on statistically significant improvement in written and simulation post-test scores. EDUCATIONAL GOALS: The objective of this educational project was to design, implement, and evaluate a curriculum relevant to an EMS system based in a LMIC, so that it could be a basis for curricula for use in similar contexts. The educational goal is to improve prehospital providers performance in common pediatric resuscitations. EDUCATIONAL METHODS: The educational methods used in this curriculum included simulation using rapid cycle deliberate practice (RCDP), didactic lectures, and hands on skills training for common pediatric scenarios. Outcomes were measured by comparing performance on written and simulation-based pre-and post-tests. RESEARCH METHODS: Participants completed written and simulation-based pre- and post-tests covering the concepts taught in the curriculum. Continuous variables (written and simulation test scores) were compared between two dependent groups (pre- and post-trainings) using paired t-tests. RESULTS: Mean written test scores increased by 11%, from 75% to 86% (p

PurposeAndecaliximab (ADX) is a monoclonal antibody that inhibits matrix metalloproteinase 9, an extracellular enzyme involved in matrix remodeling, tumor growth, and metastases. A phase I and Ib study of modified oxaliplatin, leucovorin, and fluorouracil (mFOLFOX6) with ADX revealed encouraging antitumor activity in patients with gastric or gastroesophageal junction (GEJ) adenocarcinoma.Materials and methodsThis phase III, randomized, double-blinded, placebo (PBO)-controlled multicenter study investigated the efficacy and safety of mFOLFOX6 with and without ADX in patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma. Random assignment was 1:1 to mFOLFOX6 + ADX or mFOLFOX6 + PBO. ADX/PBO 800 mg was infused on days 1 and 15 of each 28-day cycle. Protocol therapy was given until disease progression or intolerance. The primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), objective response rate (RECIST 1.1), and safety.ResultsBetween September 2015 and May 2017, 432 patients were randomly assigned, 218 to ADX and 214 to PBO. The median OS was 12.5 versus 11.8 months in the ADX and PBO groups, respectively. The median PFS was 7.5 versus 7.1 months in the ADX and PBO groups, respectively. The objective response rate was 51% in the ADX group and 41% in the PBO group. Among the subgroup analyses, patients of age ≥ 65 years had an improved OS and PFS with ADX versus PBO; the P values and CIs were not adjusted for multiplicity. There were no meaningful differences in the safety profile of the ADX versus PBO groups.ConclusionThe addition of ADX to mFOLFOX6 did not improve OS in unselected patients with untreated human epidermal growth factor receptor 2-negative gastric or GEJ adenocarcinoma.

[This corrects the article DOI: 10.1371/journal.pone.0054014.].

BackgroundMatrix metalloproteinase 9 (MMP9) expression in the tumor microenvironment is implicated in multiple protumorigenic processes. Andecaliximab (GS-5745), a monoclonal antibody targeting MMP9 with high affinity and selectivity, was evaluated in combination with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma.Patients and methodsThis phase I study was completed in two parts: part A was a dose-finding, monotherapy phase that enrolled patients with advanced solid tumors, and part B examined andecaliximab in combination with chemotherapy in specific patient cohorts. In the cohort of patients with pancreatic adenocarcinoma (n = 36), andecaliximab 800 mg every 2 weeks was administered in combination with gemcitabine and nab-paclitaxel. Patients were treated until unacceptable toxicity, withdrawal of consent, disease progression, or death. Efficacy, safety, and biomarker assessments were performed.ResultsAndecaliximab combined with gemcitabine and nab-paclitaxel appeared to be well tolerated and did not demonstrate any unusual toxicities in patients with pancreatic adenocarcinoma. The most common treatment-emergent adverse events were fatigue (75.0%), alopecia (55.6%), peripheral edema (55.6%), and nausea (50.0%). Median progression-free survival was 7.8 months (90% confidence interval, 6.9-11.0) with an objective response rate of 44.4% and median duration of response of 7.6 months. Maximal andecaliximab target binding, defined as undetectable, andecaliximab-free MMP9 in plasma, was observed.ConclusionAndecaliximab in combination with gemcitabine and nab-paclitaxel demonstrates a favorable safety profile and clinical activity in patients with advanced pancreatic adenocarcinoma.Implications for practiceThe combination of andecaliximab, a novel, first-in-class inhibitor of matrix metalloproteinase 9, with gemcitabine and nab-paclitaxel in patients with advanced pancreatic adenocarcinoma provided a median progression-free survival of 7.8 months and objective response rate of 44.4%. The majority of systemic biomarkers related to matrix metalloproteinase 9 activity and immune suppression increased at 2 months, whereas biomarkers related to tumor burden decreased. Although this study demonstrates promising results with andecaliximab plus chemotherapy in patients with advanced pancreatic adenocarcinoma, andecaliximab was not associated with a survival benefit in a phase III study in patients with advanced gastric/gastroesophageal junction carcinoma.

BackgroundMcKesson's InterQual criteria are widely used in hospitals to determine if patients should be classified as observation or inpatient status, but the accuracy of the criteria is unknown.ObjectiveWe sought to determine whether InterQual criteria accurately predicted length of stay (LOS) in older patients with syncope.MethodsWe conducted a secondary analysis of a cohort study of adults ≥60 years of age who had syncope. We calculated InterQual criteria and classified the patient as observation or inpatient status. Outcomes were whether LOS were less than or greater than 2 midnights.ResultsWe analyzed 2361 patients; 1227 (52.0%) patients were male and 1945 (82.8%) were white, with a mean age of 73.2 ± 9.0 years. The median LOS was 32.6 h (interquartile range 24.2-71.8). The sensitivity of InterQual criteria for LOS was 60.8% (95% confidence interval 57.9-63.6%) and the specificity was 47.8% (95% confidence interval 45.0-50.5%).ConclusionsIn older adults with syncope, those who met InterQual criteria for inpatient status had longer LOS compared with those who did not; however, the accuracy of the criteria to predict length of stay over 2 days is poor, with a sensitivity of 60% and a specificity of 48%. Future research should identify criteria to improve LOS prediction.

Study objectiveOlder adults with syncope are commonly treated in the emergency department (ED). We seek to derive a novel risk-stratification tool to predict 30-day serious cardiac outcomes.MethodsWe performed a prospective, observational study of older adults (≥60 years) with unexplained syncope or near syncope who presented to 11 EDs in the United States. Patients with a serious diagnosis identified in the ED were excluded. We collected clinical and laboratory data on all patients. Our primary outcome was 30-day all-cause mortality or serious cardiac outcome.ResultsWe enrolled 3,177 older adults with unexplained syncope or near syncope between April 2013 and September 2016. Mean age was 73 years (SD 9.0 years). The incidence of the primary outcome was 5.7% (95% confidence interval [CI] 4.9% to 6.5%). Using Bayesian logistic regression, we derived the FAINT score: history of heart failure, history of cardiac arrhythmia, initial abnormal ECG result, elevated pro B-type natriuretic peptide, and elevated high-sensitivity troponin T. A FAINT score of 0 versus greater than or equal to 1 had sensitivity of 96.7% (95% CI 92.9% to 98.8%) and specificity 22.2% (95% CI 20.7% to 23.8%), respectively. The FAINT score tended to be more accurate than unstructured physician judgment: area under the curve 0.704 (95% CI 0.669 to 0.739) versus 0.630 (95% CI 0.589 to 0.670).ConclusionAmong older adults with syncope or near syncope of potential cardiac cause, a FAINT score of zero had a reasonably high sensitivity for excluding death and serious cardiac outcomes at 30 days. If externally validated, this tool could improve resource use for this common condition.

BACKGROUND: As emergency medical services (EMS) systems develop globally in resource-limited settings, equipping providers with paediatric training is essential. Low-fidelity simulation-based training is an effective modality for training healthcare workers, though limited data exist on the impact of such training programmes. The objective of this study was to evaluate the paediatric portion of a simulation-based curriculum for prehospital providers in Botswana. METHODS: This was a prospective cohort study of EMS providers from more populated regions of Botswana, who attended a 2-day training that included didactic lectures, hands-on skills stations and low-fidelity simulation training. We collected data on participant self-efficacy with paediatric knowledge and skills and performance on both written and simulation-based tests. Self-efficacy and test data were analysed, and qualitative course feedback was summarised. RESULTS: Thirty-one EMS providers participated in the training. Median self-efficacy levels increased for 13/15 (87%) variables queried. The most notable improvements were observed in airway management, newborn resuscitation and weight estimation. Mean written test scores increased by 10.6%, while mean simulation test scores increased by 21.5% (p

Ill and injured children have unique needs that can be magnified when the child's ailment is serious or life-threatening. This is especially true in the out-of-hospital environment. Providing high-quality out-of-hospital care to children requires an emergency medical services (EMS) system infrastructure designed to support the care of pediatric patients. As in the emergency department setting, it is important that all EMS agencies have the appropriate resources, including physician oversight, trained and competent staff, education, policies, medications, equipment, and supplies, to provide effective emergency care for children. Resource availability across EMS agencies is variable, making it essential that EMS medical directors, administrators, and personnel collaborate with outpatient and hospital-based pediatric experts, especially those in emergency departments, to optimize prehospital emergency care for children. The principles in the policy statement "Pediatric Readiness in Emergency Medical Services Systems" and this accompanying technical report establish a foundation on which to build optimal pediatric care within EMS systems and serve as a resource for clinical and administrative EMS leaders.

BackgroundSyncope is a common chief complaint among older adults in the Emergency Department (ED), and orthostatic vital signs are often a part of their evaluation. We assessed whether abnormal orthostatic vital signs in the ED are associated with composite 30-day serious outcomes in older adults presenting with syncope.MethodsWe performed a secondary analysis of a prospective, observational study at 11 EDs in adults ≥ 60 years who presented with syncope or near syncope. We excluded patients lost to follow up. We used the standard definition of abnormal orthostatic vital signs or subjective symptoms of lightheadedness upon standing to define orthostasis. We determined the rate of composite 30-day serious outcomes, including those during the index ED visit, such as cardiac arrhythmias, myocardial infarction, cardiac intervention, new diagnosis of structural heart disease, stroke, pulmonary embolism, aortic dissection, subarachnoid hemorrhage, cardiopulmonary resuscitation, hemorrhage/anemia requiring transfusion, with major traumatic injury from fall, recurrent syncope, and death) between the groups with normal and abnormal orthostatic vital signs.ResultsThe study cohort included 1974 patients, of whom 51.2% were male and 725 patients (37.7%) had abnormal orthostatic vital signs. Comparing those with abnormal to those with normal orthostatic vital signs, we did not find a difference in composite 30-serious outcomes (111/725 (15.3%) vs 184/1249 (14.7%); unadjusted odds ratio, 1.05 [95%CI, 0.81-1.35], p = 0.73). After adjustment for gender, coronary artery disease, congestive heart failure (CHF), history of arrhythmia, dyspnea, hypotension, any abnormal ECG, physician risk assessment, medication classes and disposition, there was no association with composite 30-serious outcomes (adjusted odds ratio, 0.82 [95%CI, 0.62-1.09], p = 0.18).ConclusionsIn a cohort of older adult patients presenting with syncope who were able to have orthostatic vital signs evaluated, abnormal orthostatic vital signs did not independently predict composite 30-day serious outcomes.