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With advancements in biomarkers and momentum in precision medicine, biomarker-guided trials such as basket trials and umbrella trials have been developed under the master protocol framework. A master protocol refers to a single, overarching design developed to evaluate multiple hypotheses with the general goal of improving the efficiency of trial evaluation. One type of master protocol is the basket trial, in which a targeted therapy is evaluated for multiple diseases that share common molecular alterations or risk factors that may help predict whether the patients will respond to the given therapy. Another variant of a master protocol is the umbrella trial, in which multiple targeted therapies are evaluated for a single disease that is stratified into multiple subgroups based on different molecular or other predictive risk factors. Both designs follow the core principle of precision medicine-to tailor intervention strategies based on the patient's risk factor(s) that can help predict whether they will respond to a specific treatment. There have been increasing numbers of basket and umbrella trials, but they are still poorly understood. This article reviews common characteristics of basket and umbrella trials, key trials and recent US Food and Drug Administration approvals for precision oncology, and important considerations for clinical readers when critically evaluating future publications on basket trials and umbrella trials and for researchers when designing these clinical trials.
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Ensayos Clínicos como Asunto/métodos , Oncología Médica/métodos , Neoplasias/terapia , Humanos , Medicina de Precisión/métodos , Factores de RiesgoRESUMEN
BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and lethal arrhythmia. Ryanodine receptor 2 (RYR2) mutation accounts for â¼60% of CPVT patients which is inherited in an autosomal dominant pattern. OBJECTIVE: This study aimed to identify CPVT-related mutations and clinical characteristics among Taiwanese CPVT patients and compare to other cohorts worldwide. METHODS: Clinical and genetic data were obtained from the Sudden Arrhythmia Death Syndrome Registry in Taiwan (SADS-TW). Forty clinically diagnosed Taiwanese CPVT patients were included. RESULTS: This is the first nationwide CPVT cohort in Taiwan. Among the 29 Taiwanese patients with CPVT-related gene mutations, 55% had RYR2 mutations, a rate similar to other ethnicities. Three out of 12 RYR2 variants were unreported. Exercise-induced symptoms including syncope and cardiac arrest were more frequent in East Asian cohorts (Taiwanese 79%, Japanese 91%), compared to Caucasian cohorts (59%) (p = 0.002). CONCLUSION: The discovery of diverse RYR2 mutations in the Taiwanese CVPT population demonstrates the importance of genetic testing in different ethnicities.
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INTRODUCTION: Olanzapine use for chemotherapy-induced nausea and vomiting (CINV) in hematological malignancies, for multi-day chemotherapy, and with a steroid-sparing antiemetic strategy is poorly understood. This study investigated if olanzapine is associated with improved prevention of CINV when added to a steroid-sparing antiemetic regimen in patients with acute leukemia receiving intensive, moderately emetogenic, multi-day chemotherapy. METHODS: This was a single-center, retrospective cohort study in patients with acute leukemia. Patients who received olanzapine for CINV prevention were compared to those who did not. All patients received a 5-HT3 antagonist. Adult patients receiving moderately emetogenic, multi-day, intensive chemotherapy for acute leukemia were included. Patients were excluded if they received steroids greater than physiological doses during the study period. The primary endpoint was the complete response of CINV (no emesis or rescue antiemetic usage). RESULTS: This study included 58 patients, 12 patients received olanzapine and 46 patients were in the control group. Baseline demographics were similar. In the study population, 89.7% had acute myeloid leukemia, median age was 54 (interquartile range 42-63) years, 34.5% were female, 27.6% had prior CINV. Complete response of CINV was similar between groups, 4 (33.3%) and 15 (32.6%) patients in the olanzapine and control groups, respectively. Safety events were similar between groups. CONCLUSION: Patients with acute leukemia receiving multi-day intensive chemotherapy are at high risk for CINV. The limited data in this study suggests that olanzapine use within a steroid-sparing antiemetic regimen was well tolerated and associated with similar incidence and severity of CINV compared to the control group.
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ABSTRACT: Surgical treatment of craniosynostosis with cranial vault reconstruction in infants is associated with significant blood loss. The optimal blood management approach is an area of active investigation. Thromboelastography (TEG) was used to examine changes in coagulation after surgical blood loss that was managed by transfusion with either whole blood or blood components. Transfusion type was determined by availability of whole blood from the blood bank.This retrospective study examined differences in posttransfusion TEG maximum amplitude (MA), a measure of the maximum clot strength, for patients transfused with whole blood or blood components. We included all patients less than 24âmonths old who underwent cranial vault remodeling, received intraoperative transfusions with whole blood or blood components, and had baseline and posttransfusion TEG measured. Whole blood was requested for all patients and was preferentially used when it was available from the American Red Cross.Of 48 eligible patients, 30 received whole blood and 18 received blood components. All patients received an intraoperative antifibrinolytic agent. The posttransfusion MA in the whole blood group was 61.8âmm (IQR 59.1, 64.1) compared to 57.9âmm (IQR 50.5, 60.9) in the blood components group (Pâ=â0.010). There was a greater posttransfusion decrease in MA for patients transfused with blood components (median decrease of 7.7âmm [IQR -3.4, 6.3]) compared with whole blood (median decrease of 2.1âmm [IQR -9.6, 7.5] Pâ<â0.001).Transfusion with blood components was associated with a greater decrease in MA that was likely related to decreased postoperative fibrinogen in this group. Patients who received whole blood had higher postoperative fibrinogen levels.
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Craneosinostosis , Tromboelastografía , Transfusión de Componentes Sanguíneos , Pérdida de Sangre Quirúrgica/prevención & control , Preescolar , Craneosinostosis/cirugía , Humanos , Lactante , Estudios RetrospectivosRESUMEN
PURPOSE OF REVIEW: Children are at risk of severe hypoxemia in the perioperative period owing to their unique anatomy and physiology. Safe and effective airway management strategies are therefore key to the practice of pediatric anesthesia. The goal of this review is to highlight recent publications (2019-2021) aimed to advance pediatric airway safety and to highlight a proposed simple, pediatric-specific, universal framework to guide clinical practice. RECENT FINDINGS: Recent investigations demonstrate that infants with normal and difficult airways experience high incidences of multiple laryngoscopy attempts and resulting hypoxemia. Video laryngoscopy may improve tracheal intubation first attempt success rate in infants with normal airways. In infants with difficult airways, standard blade video laryngoscopy is associated with higher first attempt success rates over non-standard blade video laryngoscopy. Recent studies in children with Pierre Robin sequence and mucopolysaccharidoses help guide airway equipment and technique selection. Department airway leads and hospital difficult airway services are necessary to disseminate knowledge, lead quality improvement initiatives, and promote evidence-based practice guidelines. SUMMARY: Pediatric airway management morbidity is a common problem in pediatric anesthesia. Improvements in individual practitioner preparation and management strategies as well as systems-based policies are required. A simple, pediatric-specific, universal airway management framework can be adopted for safe pediatric anesthesia practice.
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Laringoscopios , Manejo de la Vía Aérea , Niño , Humanos , Hipoxia/etiología , Hipoxia/terapia , Lactante , Intubación Intratraqueal/efectos adversos , LaringoscopíaRESUMEN
The mechanisms underlying mammalian neural tube closure remain poorly understood. We report a unique cellular process involving multicellular rosette formation, convergent cellular protrusions, and F-actin cable network of the non-neural surface ectodermal cells encircling the closure site of the posterior neuropore, which are demonstrated by scanning electron microscopy and genetic fate mapping analyses during mouse spinal neurulation. These unique cellular structures are severely disrupted in the surface ectodermal transcription factor Grhl3 mutants that exhibit fully penetrant spina bifida. We propose a novel model of mammalian neural tube closure driven by surface ectodermal dynamics, which is computationally visualized.
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Actinas/metabolismo , Ectodermo/embriología , Defectos del Tubo Neural/embriología , Tubo Neural/embriología , Neurulación , Actinas/análisis , Animales , Proteínas de Unión al ADN/genética , Ectodermo/anomalías , Ectodermo/metabolismo , Ectodermo/ultraestructura , Ratones , Mutación , Tubo Neural/anomalías , Tubo Neural/metabolismo , Tubo Neural/ultraestructura , Defectos del Tubo Neural/genética , Defectos del Tubo Neural/metabolismo , Disrafia Espinal/embriología , Disrafia Espinal/genética , Disrafia Espinal/metabolismo , Columna Vertebral/anomalías , Columna Vertebral/embriología , Columna Vertebral/metabolismo , Columna Vertebral/ultraestructura , Factores de Transcripción/genéticaRESUMEN
BACKGROUND: The AABB (American Association of Blood Banks) and the College of American Pathologists (CAP) regulations call on blood banks to address the risk of misidentification of a patient's blood type, which can result in transfusion of a mismatched product. Transfusion of mismatched blood product is potentially fatal due to acute hemolytic transfusion reaction and is considered a preventable event. CAP regulations outline options to reduce risk of mistransfusion by either documenting the ABO group of the intended recipient on a second sample collected at a separate phlebotomy, or utilizing a mechanical barrier system or electronic identification verification system that ensures the patient from whom the pretransfusion specimen was collected is the same patient who is about to be transfused. STUDY DESIGN AND METHODS: An electronic or barrier system was not available for implementation at our institution, therefore we developed a protocol for a two-sample verification system. The first determination is performed on a current sample and the second by one of the following methods: (a) comparison with previous laboratory records, (b) testing a second sample collected at a time different from the first sample (i.e., laboratory specimen available with a different timestamp, or a new blood sample). RESULTS: We improved our transfusion process and implemented a policy to require a second sample to confirm a patient's blood type. We also implemented workflows to obtain blood type confirmation from history of a second blood type result from previous laboratory records, including a policy to accept previous blood type records from an outside laboratory. CONCLUSIONS: We describe a practice change for two-sample verification for type and screen in a large-scale pediatric hospital. We outline specific workflows for pre-operative and emergency transfusion scenarios, and pediatric-specific challenges.
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Bancos de Sangre , Incompatibilidad de Grupos Sanguíneos , Tipificación y Pruebas Cruzadas Sanguíneas , Transfusión Sanguínea , Hospitales Pediátricos , Reacción a la Transfusión/prevención & control , Niño , HumanosRESUMEN
The severe acute respiratory syndrome coronavirus 2 (coronavirus disease 2019 [COVID-19]) pandemic has challenged medical systems and clinicians globally to unforeseen levels. Rapid spread of COVID-19 has forced clinicians to care for patients with a highly contagious disease without evidence-based guidelines. Using a virtual modified nominal group technique, the Pediatric Difficult Intubation Collaborative (PeDI-C), which currently includes 35 hospitals from 6 countries, generated consensus guidelines on airway management in pediatric anesthesia based on expert opinion and early data about the disease. PeDI-C identified overarching goals during care, including minimizing aerosolized respiratory secretions, minimizing the number of clinicians in contact with a patient, and recognizing that undiagnosed asymptomatic patients may shed the virus and infect health care workers. Recommendations include administering anxiolytic medications, intravenous anesthetic inductions, tracheal intubation using video laryngoscopes and cuffed tracheal tubes, use of in-line suction catheters, and modifying workflow to recover patients from anesthesia in the operating room. Importantly, PeDI-C recommends that anesthesiologists consider using appropriate personal protective equipment when performing aerosol-generating medical procedures in asymptomatic children, in addition to known or suspected children with COVID-19. Airway procedures should be done in negative pressure rooms when available. Adequate time should be allowed for operating room cleaning and air filtration between surgical cases. Research using rigorous study designs is urgently needed to inform safe practices during the COVID-19 pandemic. Until further information is available, PeDI-C advises that clinicians consider these guidelines to enhance the safety of health care workers during airway management when performing aerosol-generating medical procedures. These guidelines have been endorsed by the Society for Pediatric Anesthesia and the Canadian Pediatric Anesthesia Society.
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Manejo de la Vía Aérea/métodos , Anestesiología/métodos , Infecciones por Coronavirus/terapia , Intubación Intratraqueal/métodos , Pediatría/métodos , Neumonía Viral/terapia , Adolescente , Anestesia/métodos , Anestesiología/normas , COVID-19 , Niño , Preescolar , Consenso , Guías como Asunto , Humanos , Lactante , Recién Nacido , Control de Infecciones , Transmisión de Enfermedad Infecciosa de Paciente a Profesional/prevención & control , Intubación Intratraqueal/normas , Pandemias , Pediatría/normasRESUMEN
The Bayesian paradigm provides an ideal platform to update uncertainties and carry them over into the future in the presence of data. Bayesian predictive power (BPP) reflects our belief in the eventual success of a clinical trial to meet its goals. In this paper we derive mathematical expressions for the most common types of outcomes, to make the BPP accessible to practitioners, facilitate fast computations in adaptive trial design simulations that use interim futility monitoring, and propose an organized BPP-based phase II-to-phase III design framework.
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The above article has an error in Figure 6 online (already correct in the PDF version) including the Graphical abstract figure. The original article has been corrected.
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OBJECTIVE: To present a detailed exploratory data analysis for critically investigating the patterns in medical doctor (MD) to disposition time, pre and post 24/7/365 attending radiologist coverage, for patients presenting to an emergency department (ED). MATERIALS AND METHODS: The process involved presenting several modeling techniques. To share an understanding of concepts and techniques, we used proportions, medians, and means, Mann-Whitney U test, Kaplan-Meier's (KM) survival analysis, linear and log-linear regression, log-ranked test, Cox proportional hazards model, Weibull parametric survival models and tertile analysis. Retrospective chart review was conducted to obtain a data set which was used to determine the trends in MD to disposition time. Data comprised of patients who had visited the emergency department (ED) during two distinct time periods and whose imaging studies were read by an attending emergency and trauma radiologist. RESULTS: Median provided more insight into the data as compared with the mean. The Mann-Whitney U test was appropriate to evaluate MD to disposition time, but provided limited information. The Kaplan-Meier (KM) was able to offer more insight into the data since it did not assume an underlying model and that is the reason why it was appropriate. However, KM had limited ability to handle measured confounders and was unable to describe the magnitude of difference between curves. The Cox proportional hazards semi-parametric model or some other parametric model such as the Weibull could handle multiple measured confounders and described the magnitude of difference between two (survival) groups in the data set. However, both methods assumed underlying models that may not apply to the data set such as the one used in this study. Linear regression was unlikely to be appropriate due to the shape of survival time distributions, but log transforming the outcome could address the distribution issue. Nearly all the results of the KM subgroup analyses were consistent with the results of the log-transformed linear regression subgroup analyses and the interpretation of the results was the same for both. CONCLUSION: Different statistical procedures may be applied to conduct exploratory subgroup analysis for a data set from a pre and post 24/7/365 attending coverage model. This could guide potential areas of further research to compare trends in MD to disposition time in ED. Pattern analysis provides evidence for various stakeholders to rethink the discourse about trends in MD to disposition time, pre and post 24/7/365 attending coverage. Graphical Illustration: The role of Emergency and Trauma Radiology in an Emergency Department.
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Ciencia de los Datos/métodos , Servicio de Urgencia en Hospital/organización & administración , Modelos Estadísticos , Radiólogos/estadística & datos numéricos , Carga de Trabajo/estadística & datos numéricos , Competencia Clínica , Humanos , Estudios Retrospectivos , Flujo de TrabajoRESUMEN
Background: Maximal dosing of early antimicrobials with high loading and maintenance doses may optimize pharmacokinetic parameters to achieve and maintain therapeutic concentrations at the site of infection in septic shock. Little is known about the current practice of early antimicrobial dosing in septic shock. Objective: To characterize early antimicrobial dosing in patients in the resuscitation phase of septic shock. Methods: This retrospective cohort study included patients admitted to the medical intensive care unit (ICU) with septic shock. The primary outcome was the percentage of early antibiotic orders that were maximal or conservative during the resuscitation (0 to 48 hours) phase based on predefined dosing criteria. The secondary outcomes were the correlations of different dosing strategies on hospital length of stay (LOS), ICU LOS, and hospital mortality. Results: This study evaluated 161 patients and 692 antibiotic orders; 504 (72.8%) of the orders during the resuscitation phase were conservative. There were no differences in mortality (odds ratio = 0.66; 95% confidence interval = 0.35-1.25; P = .20), hospital LOS (median = 20 [interquartile range (IQR) = 10-34] vs 19 [IQR = 11-32] days; P = .93), or ICU LOS (median = 8 [IQR = 5-16] vs 9 [IQR = 5-15] days; P = .63) between maximal and conservative dosing groups, respectively, in the resuscitation phase. Limitations of this study included the use of institution-specific antimicrobial dosing guidelines and its retrospective nature. Conclusions: Early antibiotic dosing is conservative for a majority of patients in septic shock. Future studies are needed to evaluate the impact of dosing strategy on patient-centered outcomes in septic shock.
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OBJECTIVES: To develop and test the usability and feasibility of a customizable mobile application (app) designed to help educate patients about their oral anticancer medications (OAMs) and regimens. SETTING: Outpatient cancer center and oncology pharmacy for urban, Midwestern academic health system. PRACTICE DESCRIPTION: Clinically-supervised educational intervention to support patients learning about OAMs. PRACTICE INNOVATION: With input from patient partners, our interdisciplinary team designed the first known tablet-based educational app that can interface with a patient's electronic medical record. The app is based on learning style and adherence theories and is customizable for individually prescribed OAMs. The app can accommodate multiple learning styles through text at 6th-grade reading level, pictures, animations, and audio voiceovers. Functionalities include interactive educational modules on 11 OAMs and case-based patient stories on common barriers to OAM adherence. EVALUATION: Early phase testing provided the opportunity to observe the user interface with the app and app functionality. Data were summarized descriptively from observations and comments of patient subjects. RESULTS: Thirty patient subjects provided input-19 in phase 1 usability testing and 11 in phase 2 feasibility testing. Comments provided by patient subjects during usability testing were largely positive. Responses included self-identification with patient stories, usefulness of drug information, preferences for text messages, and app limitations (e.g., perceived generational digital divide in technology use and potential patient inability to receive text messages). Using their feedback, modifications were made to the prototype app. Responses in feasibility testing demonstrated the app's usefulness across a wide range of ages. Highest opinion ratings on app usefulness were stated by patients who were newer to OAM therapy. CONCLUSION: User feedback suggests the potential benefit of the app as a tool to help patients with cancer, particularly after the first months for those starting new OAM regimens. Processes and lessons learned are transferable to other settings.
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Aplicaciones Móviles/tendencias , Neoplasias/tratamiento farmacológico , Educación del Paciente como Asunto/tendencias , Adulto , Anciano , Registros Electrónicos de Salud , Retroalimentación , Femenino , Humanos , Masculino , Persona de Mediana Edad , Atención Dirigida al Paciente , Automanejo , Diseño de SoftwareRESUMEN
Development of medicines in rare oncologic patient populations are growing, but well-powered randomized controlled trials are typically extremely challenging or unethical to conduct in such settings. External control arms using real-world data are increasingly used to supplement clinical trial evidence where no or little control arm data exists. The construction of an external control arm should always aim to match the population, treatment settings and outcome measurements of the corresponding treatment arm. Yet, external real-world data is typically fraught with limitations including missing data, measurement error and the potential for unmeasured confounding given a nonrandomized comparison. Quantitative bias analysis (QBA) comprises a collection of approaches for modelling the magnitude of systematic errors in data which cannot be addressed with conventional statistical adjustment. Their applications can range from simple deterministic equations to complex hierarchical models. QBA applied to external control arm represent an opportunity for evaluating the validity of the corresponding comparative efficacy estimates. We provide a brief overview of available QBA approaches and explore their application in practice. Using a motivating example of a comparison between pralsetinib single-arm trial data versus pembrolizumab alone or combined with chemotherapy real-world data for RET fusion-positive advanced non-small cell lung cancer (aNSCLC) patients (1-2% among all NSCLC), we illustrate how QBA can be applied to external control arms. We illustrate how QBA is used to ascertain robustness of results despite a large proportion of missing data on baseline ECOG performance status and suspicion of unknown confounding. The robustness of findings is illustrated by showing that no meaningful change to the comparative effect was observed across several 'tipping-point' scenario analyses, and by showing that suspicion of unknown confounding was ruled out by use of E-values. Full R code is also provided.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Sesgo , Proyectos de Investigación , Protocolos ClínicosRESUMEN
INTRODUCTION: Graves' ophthalmopathy (GO) is an autoimmune inflammatory disorder observed in a substantial proportion of patients with Graves' disease (GD), with debilitating symptoms of disfiguring, periorbital pain, dry eyes, diplopia, and even visual disturbances. Previous studies involving Western populations have noted discrepancies in risk factors for GO. Therefore, this study aimed to determine the risk factors for GO development and the protective effect of statins in newly diagnosed patients with GD in Taiwan. METHODS: This retrospective case-control study was based on a tertiary center cohort involving patients with GD diagnosed between 2010 and 2019 at the National Taiwan University Hospital (n = 11,035). Patients who were diagnosed or treated elsewhere, had been followed up for less than 6 months or were with a diagnosis of orbital tumor were excluded. Overall, 3578 patients with GD met the inclusion criteria. Univariate and multivariate logistic regression analyses were used to ascertain the odds ratio (OR) of developing GO, with adjustment for sociodemographic factors, interventions for managing GD and thyroid hormone levels, to determine protective and risk factors for GO. RESULTS: In our multivariate model, the use of statins reduced the risk of GO development (OR 0.2; 95% confidence interval [CI] 0.08-0.50; p < 0.001). Thyroid dysfunction including hyperthyroidism (OR 4.2; 95% CI 2.97-5.88; p < 0.001) and hypothyroidism (OR 4.7; 95% CI 3.02-7.19; p < 0.001) was associated with an increased risk of developing GO. Smoking status and lipid profile were not risk factors in our cohort. CONCLUSION: In newly diagnosed patients with GD, the use of statins decreased the risk of developing GO by 80%, whereas serum lipid levels were not considered risk factors. Further nationwide population-based studies may help clarify the differences in risk factors between various ethnic groups. TRAIL REGISTRATION: This trial was approved by the Research Ethics Committee of National Taiwan University Hospital (202202066RINC), retrospectively registered from January 1, 2010 to December 31, 2019.
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OBJECTIVE: To use large-scale electronic health record (EHR) data to develop machine learning models predicting malignant transformation of oral lesions. METHODS: A multi-institutional health system database was used to identify a retrospective cohort of patients with biopsied oral lesions. The primary outcome was malignant transformation. Chart review and automated system database queries were used to identify a range of demographic, clinical, and pathologic variables. Machine learning was used to develop predictive models for progression to malignancy. RESULTS: There were 2192 patients with a biopsied oral lesion, of whom 1232 had biopsy proven oral dysplasia. There was malignant transformation in 34% of patients in the oral lesions dataset, and in 54% of patients in the dysplasia subset. Multiple machine learning-based models were trained on the data in two experiments, (a) including all patients with biopsied oral lesions and (b) including only patients with biopsy-proven dysplasia. In the first experiment, the best machine learning models predicted malignant transformation among the biopsied oral lesions with an area under the curve (AUC) of 86%. In the second experiment, the random forest model predicted malignant transformation among lesions with dysplasia with an AUC of 0.75. The most influential features were dysplasia grade and the presence of multiple lesions, with smaller influences from other features including anemia, histopathologic description of atypia, and other prior cancer history. CONCLUSION: With diverse features from EHR data, machine learning approaches are feasible and allow for generation of models that predict which oral lesions are likely to progress to malignancy. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:1156-1162, 2023.
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Neoplasias , Humanos , Estudios Retrospectivos , Biopsia , Hiperplasia , Aprendizaje AutomáticoRESUMEN
Cytokinesis in plants is fundamentally different from that in animals and fungi. In plant cells, a cell plate forms through the fusion of cytokinetic vesicles and then develops into the new cell wall, partitioning the cytoplasm of the dividing cell. The formation of the cell plate entails multiple stages that involve highly orchestrated vesicle accumulation, fusion and membrane maturation, which occur concurrently with the timely deposition of polysaccharides such as callose, cellulose and cross-linking glycans. This review summarizes the major stages in cytokinesis, endomembrane components involved in cell plate assembly and its transition to a new cell wall. An animation that can be widely used for educational purposes further summarizes the process.
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Pared Celular , Citocinesis , Pared Celular/metabolismo , Citoplasma/metabolismo , Células Vegetales/metabolismo , Plantas/genética , Plantas/metabolismo , Polisacáridos/metabolismoRESUMEN
Importance: There is a need to tailor treatments to patients who are most likely to derive the greatest benefit from them to improve patient outcomes and enhance cost-effectiveness of cancer therapies. Objective: To compare overall survival (OS) between patients with a current or former history of smoking with patients who never smoked and initiated pembrolizumab monotherapy as first-line (1L) treatment for advanced non-small lung cancer (NSCLC). Design, Setting, and Participants: This retrospective cohort study compared patients diagnosed with advanced NSCLC aged 18 or higher selected from a nationwide real-world database originating from more than 280 US cancer clinics. The study inclusion period was from January 1, 2011, to October 1, 2019. Exposures: Smoking status at the time of NSCLC diagnosis. Main Outcomes and Measures: OS measured from initiation of 1L pembrolizumab monotherapy. Results: In this retrospective cohort study, a total of 1166 patients (median [IQR] age, 72.9 [15.3] years; 581 [49.8%] men and 585 [50.2%] women) were assessed in the primary analysis, including 91 patients [7.8%] with no history of smoking (ie, never-smokers) and 1075 patients [92.2%] who currently or formerly smoked (ie, ever-smokers). Compared with ever-smokers, never-smokers were older (median age [IQR] of 78.2 [12.0] vs 72.7 [15.5] years), more likely to be female (61 [67.0%] vs 524 [48.7%]) and to have been diagnosed with nonsquamous tumor histology (70 [76.9%] vs 738 [68.7%]). After adjustment for baseline covariates, ever-smokers who initiated 1L pembrolizumab had significantly prolonged OS compared to never-smokers (median OS: 12.8 [10.9-14.6] vs 6.5 [3.3-13.8] months; hazard ratio (HR): 0.69 [95% CI, 0.50-0.95]). This trend was observed across all sensitivity analyses for the 1L pembrolizumab cohort, but not for initiators of 1L platinum chemotherapy, for which ever-smokers showed significantly shorter OS compared with never-smokers (HR, 1.2 [95% CI, 1.07-1.33]). Conclusions and Relevance: In patients with advanced NSCLC who received 1L pembrolizumab monotherapy in routine clinical practices in the US, patients who reported a current or former history of smoking at the time of diagnosis had consistently longer OS than never-smokers. This finding suggests that in never-smoking advanced NSCLC, 1L pembrolizumab monotherapy may not be the optimal therapy selection, and genomic testing for potential genomically matched therapies should be prioritized over pembrolizumab in never-smokers.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Anciano , Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Estudios Retrospectivos , Fumar/epidemiologíaRESUMEN
As advanced non-small cell lung cancer (aNSCLC) is being increasingly divided into rare oncogene-driven subsets, conducting randomised trials becomes challenging. Using real-world data (RWD) to construct control arms for single-arm trials provides an option for comparative data. However, non-randomised treatment comparisons have the potential to be biased and cause concern for decision-makers. Using the example of pralsetinib from a RET fusion-positive aNSCLC single-arm trial (NCT03037385), we demonstrate a relative survival benefit when compared to pembrolizumab monotherapy and pembrolizumab with chemotherapy RWD cohorts. Quantitative bias analyses show that results for the RWD-trial comparisons are robust to data missingness, potential poorer outcomes in RWD and residual confounding. Overall, the study provides evidence in favour of pralsetinib as a first-line treatment for RET fusion-positive aNSCLC. The quantification of potential bias performed in this study can be used as a template for future studies of this nature.