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1.
NPJ Precis Oncol ; 8(1): 3, 2024 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-38182677

RESUMO

EGFR tyrosine kinase inhibitors (TKIs) have transformed the treatment of EGFR-mutated non-small cell lung carcinoma (NSCLC); however, therapeutic resistance remains a clinical challenge. Acquired secondary EGFR mutations that increase ATP affinity and/or impair inhibitor binding are well-described mediators of resistance. Here we identify a de novo EGFR Y891D secondary alteration in a NSCLC with EGFR L858R. Acquired EGFR Y891D alterations were previously reported in association with resistance to first generation EGFR TKIs. Functional studies in Ba/F3 cells demonstrate reduced TKI sensitivity of EGFR L858R + Y891D, with the greatest reduction observed for first and second generation TKIs. Unlike other EGFR mutations associated with TKI resistance, Y891D does not significantly alter ATP affinity or promote steric hindrance to inhibitor binding. Our data suggest that the Y891D mutation destabilizes EGFR L858R, potentially generating a population of misfolded receptor with preserved signaling capacity but reduced sensitivity to EGFR inhibitors. These findings raise the possibility of protein misfolding as a mechanism of resistance to EGFR inhibition in EGFR-mutated NSCLC.

2.
Public Health Rep ; 139(2): 187-194, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-37204194

RESUMO

OBJECTIVE: In the absence of access to surveillance system data, single-source administrative databases are often used to study health care utilization and health outcomes among people with sickle cell disease (SCD). We compared the case definitions from single-source administrative databases with a surveillance case definition to identify people with SCD. MATERIALS AND METHODS: We used data from Sickle Cell Data Collection programs in California and Georgia (2016-2018). The surveillance case definition for SCD developed for the Sickle Cell Data Collection programs uses multiple databases, including newborn screening, discharge databases, state Medicaid programs, vital records, and clinic data. Case definitions for SCD in single-source administrative databases varied by database (Medicaid and discharge) and years of data (1, 2, and 3 years). We calculated the proportion of people meeting the surveillance case definition for SCD that was captured by each single administrative database case definition for SCD, by birth cohort, sex, and Medicaid enrollment. RESULTS: In California, 7117 people met the surveillance case definition of SCD from 2016 through 2018; 48% of this group was captured by the Medicaid case definition and 41% by the discharge case definition. In Georgia, 10 448 people met the surveillance case definition of SCD from 2016 through 2018; 45% of this group was captured by the Medicaid case definition and 51% by the discharge case definition. These proportions differed by years of data, birth cohort, and length of Medicaid enrollment. PRACTICE IMPLICATIONS: The surveillance case definition identified twice as many people with SCD as the single-source administrative database definitions during the same period, but trade-offs exist in using single administrative databases for decisions on policy and program expansion for SCD.


Assuntos
Anemia Falciforme , Recém-Nascido , Estados Unidos/epidemiologia , Humanos , Anemia Falciforme/diagnóstico , Anemia Falciforme/epidemiologia , Georgia/epidemiologia , Coleta de Dados , Alta do Paciente , Bases de Dados Factuais
5.
Chest ; 164(3): 700-716, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-36965765

RESUMO

BACKGROUND: Microvascular abnormalities and impaired gas transfer have been observed in patients with COVID-19. The progression of pulmonary changes in these patients remains unclear. RESEARCH QUESTION: Do patients hospitalized with COVID-19 without evidence of architectural distortion on structural imaging exhibit longitudinal improvements in lung function measured by using 1H and 129Xe MRI between 6 and 52 weeks following hospitalization? STUDY DESIGN AND METHODS: Patients who were hospitalized with COVID-19 pneumonia underwent a pulmonary 1H and 129Xe MRI protocol at 6, 12, 25, and 51 weeks following hospital admission in a prospective cohort study between November 2020 and February 2022. The imaging protocol was as follows: 1H ultra-short echo time, contrast-enhanced lung perfusion, 129Xe ventilation, 129Xe diffusion-weighted, and 129Xe spectroscopic imaging of gas exchange. RESULTS: Nine patients were recruited (age 57 ± 14 [median ± interquartile range] years; six of nine patients were male). Patients underwent MRI at 6 (n = 9), 12 (n = 9), 25 (n = 6), and 51 (n = 8) weeks following hospital admission. Patients with signs of interstitial lung damage were excluded. At 6 weeks, patients exhibited impaired 129Xe gas transfer (RBC to membrane fraction), but lung microstructure was not increased (apparent diffusion coefficient and mean acinar airway dimensions). Minor ventilation abnormalities present in four patients were largely resolved in the 6- to 25-week period. At 12 weeks, all patients with lung perfusion data (n = 6) showed an increase in both pulmonary blood volume and flow compared with 6 weeks, although this was not statistically significant. At 12 weeks, significant improvements in 129Xe gas transfer were observed compared with 6-week examinations; however, 129Xe gas transfer remained abnormally low at weeks 12, 25, and 51. INTERPRETATION: 129Xe gas transfer was impaired up to 1 year following hospitalization in patients who were hospitalized with COVID-19 pneumonia, without evidence of architectural distortion on structural imaging, whereas lung ventilation was normal at 52 weeks.


Assuntos
COVID-19 , Isótopos de Xenônio , Humanos , Masculino , Adulto , Pessoa de Meia-Idade , Idoso , Feminino , Estudos Prospectivos , Imageamento por Ressonância Magnética/métodos , Pulmão/diagnóstico por imagem
6.
JMIR Cancer ; 8(2): e33859, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35588361

RESUMO

BACKGROUND: Expert knowledge is often shared among multidisciplinary academic teams at tumor boards (TBs) across the country, but these conversations exist in silos and do not reach the wider oncology community. OBJECTIVE: Using an oncologist-only question and answer (Q&A) website, we sought to document expert insights from TBs at National Cancer Institute-designated Comprehensive Cancer Centers (NCI-CCCs) to provide educational benefits to the oncology community. METHODS: We designed a process with the NCI-CCCs to document and share discussions from the TBs focused on areas of practice variation on theMednet, an interactive Q&A website of over 13,000 US oncologists. The faculty translated the TB discussions into concise, non-case-based Q&As on theMednet. Answers were peer reviewed and disseminated in email newsletters to registered oncologists. Reach and engagement were measured. Following each Q&A, a survey question asked how the TB Q&As impacted the readers' practice. RESULTS: A total of 23 breast, thoracic, gastrointestinal, and genitourinary programs from 16 NCI-CCC sites participated. Between December 2016 and July 2021, the faculty highlighted 368 questions from their TBs. Q&As were viewed 147,661 times by 7381 oncologists at 3515 institutions from all 50 states. A total of 277 (75%) Q&As were viewed every month. Of the 1063 responses to a survey question on how the Q&A affected clinicians' practices, 646 (61%) reported that it confirmed their current practice, 163 (20%) indicated that a Q&A would change their future practice, and 214 (15%) reported learning something new. CONCLUSIONS: Through an online Q&A platform, academics at the NCI-CCCs share knowledge outside the walls of academia with oncologists across the United States. Access to up-to-date expert knowledge can reassure clinicians' practices, significantly impact patient care in community practices, and be a source of new knowledge and education.

7.
Clin Cancer Res ; 28(14): 3091-3103, 2022 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-35247929

RESUMO

PURPOSE: The identification of actionable oncogenic alterations has enabled targeted therapeutic strategies for subsets of patients with advanced malignancies, including lung adenocarcinoma (LUAD). We sought to assess the frequency of known drivers and identify new candidate drivers in a cohort of LUAD from patients with minimal smoking history. EXPERIMENTAL DESIGN: We performed genomic characterization of 103 LUADs from patients with ≤10 pack-year smoking history. Tumors were subjected to targeted molecular profiling and/or whole-exome sequencing and RNA sequencing in search of established and previously uncharacterized candidate drivers. RESULTS: We identified an established oncogenic driver in 98 of 103 tumors (95%). From one tumor lacking a known driver, we identified a novel gene rearrangement between OCLN and RASGRF1. The encoded OCLN-RASGRF1 chimera fuses the membrane-spanning portion of the tight junction protein occludin with the catalytic RAS-GEF domain of the RAS activator RASGRF1. We identified a similar SLC4A4-RASGRF1 fusion in a pancreatic ductal adenocarcinoma cell line lacking an activating KRAS mutation and an IQGAP1-RASGRF1 fusion from a sarcoma in The Cancer Genome Atlas. We demonstrate these fusions increase cellular levels of active GTP-RAS, induce cellular transformation, and promote in vivo tumorigenesis. Cells driven by RASGRF1 fusions are sensitive to targeting of the RAF-MEK-ERK pathway in vitro and in vivo. CONCLUSIONS: Our findings credential RASGRF1 fusions as a therapeutic target in multiple malignancies and implicate RAF-MEK-ERK inhibition as a potential treatment strategy for advanced tumors harboring these alterations. See related commentary by Moorthi and Berger, p. 2983.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Carcinogênese/genética , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Quinases de Proteína Quinase Ativadas por Mitógeno , ras-GRF1/genética
9.
Health Serv Res ; 57(3): 458-471, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-34596232

RESUMO

OBJECTIVE: To investigate (a) the magnitude of the independent associations of neighborhood-level and person-level social risk factors (SRFs) with quality, (b) whether neighborhood-level SRF associations may be proxies for person-level SRF associations, and (c) how the association of person-level SRFs and quality varies by neighborhood-level SRFs. DATA SOURCES: 2015-2016 Medicare Advantage HEDIS data, Medicare beneficiary administrative data, and 2016 American Community Survey (ACS). STUDY DESIGN: Mixed effects linear regression models (1) estimated overall inequities by neighborhood-level and person-level SRFs, (2) compared neighborhood-level associations to person-level associations, and (3) tested the interactions of person-level SRFs with corresponding neighborhood-level SRFs. DATA COLLECTION/EXTRACTION METHODS: Beneficiary-level SES and disability administrative data and five-year ACS neighborhood-level SRF information were each linked to HEDIS data. PRINCIPAL FINDINGS: For all or nearly all HEDIS measures, quality was worse in neighborhoods lower in SES and in neighborhoods with higher proportions of residents with a disability. Quality by neighborhood racial and ethnic composition was mixed. Accounting for corresponding person-level SRFs reduced neighborhood SRF associations by 25% for disability, 43% for SES, and 74%-102% for racial and ethnic groups. Person-level SRF coefficients were not consistently reduced in models that added neighborhood-level SRFs. In 19 of 35 instances, there were significant (p < 0.05) interactions between neighborhood-level and corresponding person-level SRFs. Significant interactions were always positive for disability, SES, Black, and Hispanic, indicating more negative neighborhood effects for people with SRFs that did not match their neighborhood and more positive neighborhood effects for people with SRFs that matched their neighborhood. CONCLUSIONS: Relying solely on neighborhood-level SRF models that omit similar person-level SRFs overattributes inequities to neighborhood characteristics. Neighborhood-level characteristics account for much less variation in these measures' scores than similar person-level SRFs. Inequity-reduction programs may be most effective when targeting neighborhoods with a high proportion of people with a given SRF.


Assuntos
Medicare Part C , Características de Residência , Idoso , Atenção à Saúde , Etnicidade , Humanos , Fatores de Risco , Fatores Socioeconômicos , Estados Unidos
10.
Thorax ; 76(10): 1032-1035, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-33632769

RESUMO

End points that are repeatable and sensitive to change are important in pulmonary arterial hypertension (PAH) for clinical practice and trials of new therapies. In 42 patients with PAH, test-retest repeatability was assessed using the intraclass correlation coefficient and treatment effect size using Cohen's d statistic. Intraclass correlation coefficients demonstrated excellent repeatability for MRI, 6 min walk test and log to base 10 N-terminal pro-brain natriuretic peptide (log10NT-proBNP). The treatment effect size for MRI-derived right ventricular ejection fraction was large (Cohen's d 0.81), whereas the effect size for the 6 min walk test (Cohen's d 0.22) and log10NT-proBNP (Cohen's d 0.20) were fair. This study supports further evaluation of MRI as a non-invasive end point for clinical assessment and PAH therapy trials.Trial registration number NCT03841344.


Assuntos
Hipertensão Pulmonar , Hipertensão Arterial Pulmonar , Humanos , Peptídeo Natriurético Encefálico , Fragmentos de Peptídeos , Volume Sistólico , Função Ventricular Direita , Teste de Caminhada
11.
J Gen Intern Med ; 36(7): 1847-1857, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-31713030

RESUMO

BACKGROUND: Social risk factors (SRFs) such as minority race-and-ethnicity or low income are associated with quality-of-care, health, and healthcare outcomes. Organizations might prioritize improving care for easier-to-treat groups over those with SRFs, but measuring, reporting, and further incentivizing quality-of-care for SRF groups may improve their care. OBJECTIVE: To develop, as a proof-of-concept, a Health Equity Summary Score (HESS): a succinct, easy-to-understand score that could be used to promote high-quality care to those with SRFs in Medicare Advantage (MA) health plans, which provide care for almost twenty million older and disabled Americans and collect extensive quality measure and SRF data. DESIGN: We estimated, standardized, and combined performance scores for two sets of quality measures for enrollees in 2013-2016 MA health plans, considering both current levels of care, within-plan improvement, and nationally benchmarked improvement for those with SRFs (specifically, racial-and-ethnic minority status and dual-eligibility for Medicare and Medicaid). PARTICIPANTS: All MA plans with publicly reported quality scores and 500 or more 2016 enrollees. MAIN MEASURES: Publicly reported clinical quality and patient experience measures. KEY RESULTS: Almost 90% of plans measured for MA Star Ratings received a HESS; plans serving few patients with SRFs were excluded. The summary score was moderately positively correlated with publicly reported overall Star Ratings (r = 0.66-0.67). High-scoring plans typically had sizable enrollment of both racial-and-ethnic minorities (38-42%) and dually eligible beneficiaries (29-38%). CONCLUSIONS: We demonstrated the feasibility of developing and estimating a HESS that is intended to promote and incentivize excellent care for racial-and-ethnic minorities and dually eligible MA enrollees. The HESS measures SRF-specific performance and does not simply duplicate overall plan Star Ratings. It also identifies plans that provide excellent care to large numbers of those with SRFs. Our methodology could be extended to other SRFs, quality measures, and settings.


Assuntos
Equidade em Saúde , Medicare Part C , Idoso , Etnicidade , Humanos , Grupos Minoritários , Motivação , Estados Unidos
12.
J Am Geriatr Soc ; 69(2): 485-493, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33216957

RESUMO

BACKGROUND AND OBJECTIVES: Opioid use and misuse are prevalent and remain a national crisis. This study identified beneficiary characteristics associated with filling opioid prescriptions, variation in opioid dosing, and opioid use with average daily doses (ADDs) equal to 120 morphine milligram equivalents (MMEs) or more in the 100% Medicare fee-for-service (FFS) population. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: In a cohort of FFS beneficiaries with 12 months of Medicare Part D coverage in 2016, we examined patient factors associated with filling an opioid prescription (n = 20,880,490) and variation in ADDs (n = 7,325,031) in a two-part model. Among those filling opioids, we also examined the probability of ADD equal to 120 MMEs or more via logistic regression. RESULTS: About 35% of FFS beneficiaries had one or more opioid prescription fills in 2016 and 1.5% had ADDs equal to 120 MMEs or more. Disability-eligible beneficiaries and beneficiaries with multiple chronic conditions were more likely to fill opioids, to have higher ADDs or were more likely to have ADD equal to 120 MMEs or more. Beneficiaries with chronic obstructive pulmonary disease (COPD) were more likely to fill opioids (odds ratio (OR) = 1.47, 95% confidence interval (CI) = 1.46-1.47), have higher ADDs (rate ratio = 1.06, 95% CI = 1.06-1.06) when filled and were more likely to have ADD equal to 120 MMEs or more (OR = 1.23, 95% CI = 1.21-1.24). Finally, black and Hispanic beneficiaries were less likely to fill opioids, had lower overall doses and were less likely to have ADDs equal to 120 MMEs or more compared to white beneficiaries. CONCLUSION: Several beneficiary subgroups have underappreciated risk of adverse events associated with ADD equal to 120 MMEs or more that may benefit from opioid optimization interventions that balance pain management and adverse event risk, especially beneficiaries with COPD who are at risk for respiratory depression.


Assuntos
Analgésicos Opioides , Manejo da Dor , Padrões de Prática Médica/estatística & dados numéricos , Medição de Risco , Idoso , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/efeitos adversos , Relação Dose-Resposta a Droga , Planos de Pagamento por Serviço Prestado/estatística & dados numéricos , Feminino , Humanos , Masculino , Medicare/estatística & dados numéricos , Avaliação das Necessidades , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Transtornos Relacionados ao Uso de Opioides/prevenção & controle , Manejo da Dor/métodos , Manejo da Dor/normas , Medicamentos sob Prescrição/administração & dosagem , Medicamentos sob Prescrição/efeitos adversos , Estados Unidos/epidemiologia
13.
Womens Health Issues ; 30(6): 477-483, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32994130

RESUMO

BACKGROUND: Medicare beneficiaries annually select fee-for-service Medicare or a private Medicare insurance (managed care) plan; information about plan performance on quality measures can inform their decisions. Although there is drill-down information available regarding quality variation by race and ethnicity, there remains a dearth of evidence regarding the extent to which care varies by other key beneficiary characteristics, such as gender. We measured gender differences for six patient experience measures and how gender gaps differ across Medicare plans. METHODS: We used data from 300,979 respondents to the 2015-2016 Medicare Advantage Consumer Assessment of Healthcare Providers and Systems surveys. We fit case mix-adjusted linear mixed-effects models to estimate gender differences and evaluate heterogeneity in differences across health plans. RESULTS: Nationally, women's experiences were better than men's (p < .05) by 1 percentage point on measures involving interactions with administrative staff (+1.6 percentage point for customer service) and timely access to care (+1.1 percentage point for getting care quickly), but worse on a measure that may involve negotiation with physicians (getting needed care). Gender gaps varied across plans, particularly for getting care quickly and getting needed care, where plan-level differences of up to 5 to 6 percentage points were observed. CONCLUSIONS: Although the average national differences in patient experience by gender were generally small, gender gaps were larger in some health plans and for specific measures. This finding indicates opportunities for health plans with larger gender gaps to implement quality improvement efforts.


Assuntos
Medicare Part C , Idoso , Feminino , Humanos , Masculino , Programas de Assistência Gerenciada , Avaliação de Resultados da Assistência ao Paciente , Caracteres Sexuais , Fatores Sexuais , Estados Unidos
14.
Med Care ; 58(11): 981-987, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32947510

RESUMO

BACKGROUND: Little is known about the health care experiences of American Indians and Alaska Natives (AIANs) due to limited data. OBJECTIVE: The objective of this study was to investigate the health care experiences of AIAN Medicare beneficiaries relative to non-Hispanic Whites using national survey data pooled over 5 years. SUBJECTS: A total of 1,193,248 beneficiaries who responded to the nationally representative 2012-2016 Medicare Consumer Assessment of Healthcare Providers and Systems (CAHPS) surveys. METHODS: Linear regression models predicted CAHPS measures from race and ethnicity. Scores on the CAHPS measures were linearly transformed to a 0-100 range and case-mix adjusted. Three AIAN groups were compared with non-Hispanic Whites: single-race AIANs (n=2491; 0.4% of the total sample), multiple-race AIANs (n=15,502; 1.3%), and Hispanic AIANs (n=2264; 0.2%). RESULTS: Among AIAN groups, single-race AIANs were most likely to live in rural areas and areas served by the Indian Health Service; Hispanic AIANs were most likely to be Spanish-language-preferring (P's<0.05). Compared with non-Hispanic Whites, single-race AIANs reported worse experiences with getting needed care (adjusted disparity of -5 points; a "large" difference), getting care quickly (-4 points; a "medium" difference), doctor communication (-2 points; a "small" difference), care coordination (-2 points), and customer service (-7 points; P<0.001 for all comparisons). Disparities were similar for Hispanic AIANs but more limited for multiple-race AIANs. CONCLUSIONS: Quality improvement efforts are needed to reduce disparities faced by older AIANs. These findings may assist in developing targeted efforts to address cultural, communication, and health system factors presumed to underlie disparities in health care access and customer service.


Assuntos
/estatística & dados numéricos , Disparidades em Assistência à Saúde/etnologia , Indígenas Norte-Americanos/estatística & dados numéricos , Medicare/estatística & dados numéricos , Satisfação do Paciente/estatística & dados numéricos , Idoso , Idoso de 80 Anos ou mais , Comunicação , Continuidade da Assistência ao Paciente/organização & administração , Feminino , Pesquisas sobre Atenção à Saúde , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Nível de Saúde , Humanos , Masculino , Qualidade da Assistência à Saúde/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Fatores Socioeconômicos , Fatores de Tempo , Estados Unidos , United States Indian Health Service/estatística & dados numéricos , População Branca/estatística & dados numéricos
15.
J Nucl Med ; 61(12): 1701-1707, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32948678

RESUMO

PET with 18F-FDG has been increasingly applied, predominantly in the research setting, to study drug effects and pulmonary biology and to monitor disease progression and treatment outcomes in lung diseases that interfere with gas exchange through alterations of the pulmonary parenchyma, airways, or vasculature. To date, however, there are no widely accepted standard acquisition protocols or imaging data analysis methods for pulmonary 18F-FDG PET/CT in these diseases, resulting in disparate approaches. Hence, comparison of data across the literature is challenging. To help harmonize the acquisition and analysis and promote reproducibility, we collated details of acquisition protocols and analysis methods from 7 PET centers. From this information and our discussions, we reached the consensus recommendations given here on patient preparation, choice of dynamic versus static imaging, image reconstruction, and image analysis reporting.


Assuntos
Consenso , Fluordesoxiglucose F18 , Pneumopatias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Guias de Prática Clínica como Assunto , Fluordesoxiglucose F18/administração & dosagem , Humanos , Processamento de Imagem Assistida por Computador , Injeções , Pneumopatias/fisiopatologia , Posicionamento do Paciente , Respiração
16.
Int J Chron Obstruct Pulmon Dis ; 15: 1751-1787, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32801677

RESUMO

Exacerbations of chronic obstructive pulmonary disease (COPD) are currently diagnosed based on changes in respiratory symptoms. Characterizing the imaging manifestation of exacerbations could be useful for objective diagnosis of exacerbations in the clinic and clinical trials, as well as provide a mechanism for monitoring exacerbation treatment and recovery. In this systematic review, we employed a comprehensive search across three databases (Medline, EMBASE, Web of Science) to identify studies that performed imaging of the thorax at COPD exacerbation. We included 51 from a total of 5,047 articles which met all our inclusion criteria. We used an adapted version of the Modified Newcastle-Ottawa Quality Assessment Scale for cohort studies to assess the quality of the included studies. Conclusions were weighted towards higher-quality articles. We identified a total of 36 thoracic imaging features studied at exacerbation of COPD. Studies were generally heterogeneous in their measurements and focus. Nevertheless, considering studies which performed consecutive imaging at stable state and exacerbation, which scored highest for quality, we identified salient imaging biomarkers of exacerbations. An exacerbation is characterized by airway wall and airway calibre changes, hyperinflation, pulmonary vasoconstriction and imaging features suggestive of pulmonary arterial hypertension. Most information was gained from CT studies. We present the first ever composite imaging signature of COPD exacerbations. While imaging during an exacerbation is comparatively new and not comprehensively studied, it may uncover important insights into the acute pathophysiologic changes in the cardiorespiratory system during exacerbations of COPD, providing objective confirmation of events and a biomarker of recovery and treatment response.


Assuntos
Doença Pulmonar Obstrutiva Crônica , Progressão da Doença , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico por imagem
17.
Eur J Radiol ; 130: 109182, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32702614

RESUMO

BACKGROUND: Respiratory diseases are one of the leading causes of death worldwide, yet effective treatment options remain limited. Although inflammation is thought to be a key driver in the pathogenesis and progression of several lung diseases, the underlying molecular mechanisms of lung dysfunction remain poorly understood. Imaging techniques may help to further our understanding of the pathophysiology and facilitate the translation of novel therapies. Positron Emission Tomography (PET) is a functional imaging technique which has the potential to interrogate the underlying inflammatory response. We present a systematic review of the literature summarising the emerging PET radiotracers developed to quantify pulmonary inflammation. METHOD: We performed a systematic review using the following databases: Medline, Embase, Scopus, PubMed, Web of Science and Cochrane. We included articles between 1995 and 2019 for all studies using PET radiotracers to evaluate inflammatory response in the lung. From a total of 911 articles covering both animal and human studies, two reviewers selected papers based on the inclusion/exclusion criteria and extracted data from 68 articles selected. RESULTS: 53 out of 68 papers, including both human and animal studies, were eligible for synthesis. Heterogenous study populations and differences in study design, image acquisition and analysis made data pooling unfeasible; instead, we provide a narrative synthesis. CONCLUSIONS: Currently, very few novel radiotracers targeting lung inflammation have crossed the translational gap from animal models to human studies. Nevertheless, our results highlight a handful of promising tracers which warrant further evaluation in humans. 18F-FDG has been investigated most extensively; although 18F-FDG is not a specific inflammatory tracer, human studies of several pulmonary diseases support its use as a biomarker for inflammation. Despite ongoing debate about the optimal analysis methodology for 18F-FDG lung images, standardisation of image acquisition and analysis should help to improve confidence in research outcomes. PET radiotracers can provide quantitative, targeted biomarkers which relate to the activity of molecular pathways and may expedite development of specific anti-inflammatory drugs.


Assuntos
Pneumonia/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Animais , Progressão da Doença , Fluordesoxiglucose F18/administração & dosagem , Previsões , Humanos , Pneumonia/terapia , Tomografia por Emissão de Pósitrons/tendências , Compostos Radiofarmacêuticos/administração & dosagem , Resultado do Tratamento
18.
Lancet Oncol ; 21(5): 655-663, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32251621

RESUMO

BACKGROUND: We did a phase 2 trial of pembrolizumab in patients with non-small-cell lung cancer (NSCLC) or melanoma with untreated brain metastases to determine the activity of PD-1 blockade in the CNS. Interim results were previously published, and we now report an updated analysis of the full NSCLC cohort. METHODS: This was an open-label, phase 2 study of patients from the Yale Cancer Center (CT, USA). Eligible patients were at least 18 years of age with stage IV NSCLC with at least one brain metastasis 5-20 mm in size, not previously treated or progressing after previous radiotherapy, no neurological symptoms or corticosteroid requirement, and Eastern Cooperative Oncology Group performance status less than two. Modified Response Evaluation Criteria in Solid Tumors (mRECIST) criteria was used to evaluate CNS disease; systemic disease was not required for participation. Patients were treated with pembrolizumab 10 mg/kg intravenously every 2 weeks. Patients were in two cohorts: cohort 1 was for those with PD-L1 expression of at least 1% and cohort 2 was patients with PD-L1 less than 1% or unevaluable. The primary endpoint was the proportion of patients achieving a brain metastasis response (partial response or complete response, according to mRECIST). All treated patients were analysed for response and safety endpoints. This study is closed to accrual and is registered with ClinicalTrials.gov, NCT02085070. FINDINGS: Between March 31, 2014, and May 21, 2018, 42 patients were treated. Median follow-up was 8·3 months (IQR 4·5-26·2). 11 (29·7% [95% CI 15·9-47·0]) of 37 patients in cohort 1 had a brain metastasis response. There were no responses in cohort 2. Grade 3-4 adverse events related to treatment included two patients with pneumonitis, and one each with constitutional symptoms, colitis, adrenal insufficiency, hyperglycaemia, and hypokalaemia. Treatment-related serious adverse events occurred in six (14%) of 42 patients and were pneumonitis (n=2), acute kidney injury, colitis, hypokalaemia, and adrenal insufficiency (n=1 each). There were no treatment-related deaths. INTERPRETATION: Pembrolizumab has activity in brain metastases from NSCLC with PD-L1 expression at least 1% and is safe in selected patients with untreated brain metastases. Further investigation of immunotherapy in patients with CNS disease from NSCLC is warranted. FUNDING: Merck and the Yale Cancer Center.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antígeno B7-H1/genética , Neoplasias Encefálicas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Biomarcadores Tumorais/genética , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica
19.
Respir Res ; 21(1): 75, 2020 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-32216814

RESUMO

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease with poor prognosis and a significant unmet medical need. This study evaluated the safety, pharmacokinetics (PK) and target engagement in the lungs, of GSK3008348, a novel inhaled alpha-v beta-6 (αvß6) integrin inhibitor, in participants with IPF. METHODS: This was a phase 1b, randomised, double-blind (sponsor unblind) study, conducted in the UK (two clinical sites, one imaging unit) between June 2017 and July 2018 (NCT03069989). Participants with a definite or probable diagnosis of IPF received a single nebulised dose of 1000 mcg GSK3008348 or placebo (ratio 5:2) in two dosing periods. In period 1, safety and PK assessments were performed up to 24 h post-dose; in period 2, after a 7-day to 28-day washout, participants underwent a total of three positron emission tomography (PET) scans: baseline, Day 1 (~ 30 min post-dosing) and Day 2 (~ 24 h post-dosing), using a radiolabelled αvß6-specific ligand, [18F]FB-A20FMDV2. The primary endpoint was whole lung volume of distribution (VT), not corrected for air volume, at ~ 30 min post-dose compared with pre-dose. The study success criterion, determined using Bayesian analysis, was a posterior probability (true % reduction in VT > 0%) of ≥80%. RESULTS: Eight participants with IPF were enrolled and seven completed the study. Adjusted posterior median reduction in uncorrected VT at ~ 30 min after GSK3008348 inhalation was 20% (95% CrI: - 9 to 42%). The posterior probability that the true % reduction in VT > 0% was 93%. GSK3008348 was well tolerated with no reports of serious adverse events or clinically significant abnormalities that were attributable to study treatment. PK was successfully characterised showing rapid absorption followed by a multiphasic elimination. CONCLUSIONS: This study demonstrated engagement of the αvß6 integrin target in the lung following nebulised dosing with GSK3008348 to participants with IPF. To the best of our knowledge this is the first time a target-specific PET radioligand has been used to assess target engagement in the lung, not least for an inhaled drug. TRIAL REGISTRATION: clinicaltrials.gov: NCT03069989; date of registration: 3 March 2017.


Assuntos
Butiratos/uso terapêutico , Fibrose Pulmonar Idiopática/tratamento farmacológico , Integrinas/antagonistas & inibidores , Naftiridinas/uso terapêutico , Pirazóis/uso terapêutico , Pirrolidinas/uso terapêutico , Volume de Ventilação Pulmonar/efeitos dos fármacos , Administração por Inalação , Idoso , Antígenos de Neoplasias , Teorema de Bayes , Butiratos/administração & dosagem , Butiratos/farmacocinética , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico por imagem , Masculino , Naftiridinas/administração & dosagem , Naftiridinas/farmacocinética , Nebulizadores e Vaporizadores , Tomografia por Emissão de Pósitrons , Pirazóis/administração & dosagem , Pirazóis/farmacocinética , Pirrolidinas/administração & dosagem , Pirrolidinas/farmacocinética , Resultado do Tratamento
20.
Eur J Nucl Med Mol Imaging ; 47(4): 958-966, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31897589

RESUMO

PURPOSE: Integrin αvß6 belongs to the RGD subset of the integrin family, and its expression levels are a prognostic and theranostic factor in some types of cancer and pulmonary fibrosis. This paper describes the GMP radiolabelling of the synthetic 20 amino acid peptide A20FMDV2 (NAVPNLRGDLQVLAQKVART), derived from the foot-and-mouth disease virus, and characterises the use of [18F]FB-A20FMDV2 as a high affinity, specific and selective PET radioligand for the quantitation and visualisation of αvß6 in rodent lung to support human translational studies. METHODS: The synthesis of [18F]FB-A20FMDV2 was performed using a fully automated and GMP-compliant process. Sprague-Dawley rats were used to perform homologous (unlabelled FB-A20FMDV2) and heterologous (anti-αvß6 antibody 8G6) blocking studies. In order to generate a dosimetry estimate, tissue residence times were generated, and associated tissue exposure and effective dose were calculated using the Organ Level Internal Dose Assessment/Exponential Modelling (OLINDA/EXM) software. RESULTS: [18F]FB-A20FMDV2 synthesis was accomplished in 180 min providing ~800 MBq of [18F]FB-A20FMDV2 with a molar activity of up to 150 GBq/µmol and high radiochemical purity (> 97%). Following i.v. administration to rats, [18F]FB-A20FMDV2 was rapidly metabolised with intact radiotracer representing 5% of the total radioactivity present in rat plasma at 30 min. For the homologous and heterologous block in rats, lung-to-heart SUV ratios at 30-60 min post-administration of [18F]FB-A20FMDV2 were reduced by 38.9 ± 6.9% and 56 ± 19.2% for homologous and heterologous block, respectively. Rodent biodistribution and dosimetry calculations using OLINDA/EXM provided a whole body effective dose in humans 33.5 µSv/MBq. CONCLUSION: [18F]FB-A20FMDV2 represents a specific and selective PET ligand to measure drug-associated αvß6 integrin occupancy in lung. The effective dose, extrapolated from rodent data, is in line with typical values for compounds labelled with fluorine-18 and combined with the novel fully automated and GMP-compliant synthesis and allows for clinical use in translational studies.


Assuntos
Integrinas , Roedores , Animais , Antígenos de Neoplasias , Cadeias beta de Integrinas , Integrinas/metabolismo , Pulmão/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Ratos , Ratos Sprague-Dawley , Roedores/metabolismo , Distribuição Tecidual
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