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1.
MMWR Morb Mortal Wkly Rep ; 70(36): 1249-1254, 2021 Sep 10.
Artículo en Inglés | MEDLINE | ID: mdl-34499628

RESUMEN

Although COVID-19 generally results in milder disease in children and adolescents than in adults, severe illness from COVID-19 can occur in children and adolescents and might require hospitalization and intensive care unit (ICU) support (1-3). It is not known whether the B.1.617.2 (Delta) variant,* which has been the predominant variant of SARS-CoV-2 (the virus that causes COVID-19) in the United States since late June 2021,† causes different clinical outcomes in children and adolescents compared with variants that circulated earlier. To assess trends among children and adolescents, CDC analyzed new COVID-19 cases, emergency department (ED) visits with a COVID-19 diagnosis code, and hospital admissions of patients with confirmed COVID-19 among persons aged 0-17 years during August 1, 2020-August 27, 2021. Since July 2021, after Delta had become the predominant circulating variant, the rate of new COVID-19 cases and COVID-19-related ED visits increased for persons aged 0-4, 5-11, and 12-17 years, and hospital admissions of patients with confirmed COVID-19 increased for persons aged 0-17 years. Among persons aged 0-17 years during the most recent 2-week period (August 14-27, 2021), COVID-19-related ED visits and hospital admissions in the states with the lowest vaccination coverage were 3.4 and 3.7 times that in the states with the highest vaccination coverage, respectively. At selected hospitals, the proportion of COVID-19 patients aged 0-17 years who were admitted to an ICU ranged from 10% to 25% during August 2020-June 2021 and was 20% and 18% during July and August 2021, respectively. Broad, community-wide vaccination of all eligible persons is a critical component of mitigation strategies to protect pediatric populations from SARS-CoV-2 infection and severe COVID-19 illness.


Asunto(s)
COVID-19/epidemiología , COVID-19/terapia , Servicio de Urgencia en Hospital/estadística & datos numéricos , Utilización de Instalaciones y Servicios/tendencias , Hospitalización/tendencias , Adolescente , COVID-19/prevención & control , Vacunas contra la COVID-19/administración & dosificación , Niño , Preescolar , Humanos , Lactante , Recién Nacido , Índice de Severidad de la Enfermedad , Estados Unidos/epidemiología , Cobertura de Vacunación/estadística & datos numéricos
2.
MMWR Morb Mortal Wkly Rep ; 70(35): 1228-1232, 2021 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-34473684

RESUMEN

Viral infections are a common cause of myocarditis, an inflammation of the heart muscle (myocardium) that can result in hospitalization, heart failure, and sudden death (1). Emerging data suggest an association between COVID-19 and myocarditis (2-5). CDC assessed this association using a large, U.S. hospital-based administrative database of health care encounters from >900 hospitals. Myocarditis inpatient encounters were 42.3% higher in 2020 than in 2019. During March 2020-January 2021, the period that coincided with the COVID-19 pandemic, the risk for myocarditis was 0.146% among patients diagnosed with COVID-19 during an inpatient or hospital-based outpatient encounter and 0.009% among patients who were not diagnosed with COVID-19. After adjusting for patient and hospital characteristics, patients with COVID-19 during March 2020-January 2021 had, on average, 15.7 times the risk for myocarditis compared with those without COVID-19 (95% confidence interval [CI] = 14.1-17.2); by age, risk ratios ranged from approximately 7.0 for patients aged 16-39 years to >30.0 for patients aged <16 years or ≥75 years. Overall, myocarditis was uncommon among persons with and without COVID-19; however, COVID-19 was significantly associated with an increased risk for myocarditis, with risk varying by age group. These findings underscore the importance of implementing evidence-based COVID-19 prevention strategies, including vaccination, to reduce the public health impact of COVID-19 and its associated complications.


Asunto(s)
COVID-19/complicaciones , Miocarditis/virología , Adolescente , Adulto , Anciano , COVID-19/epidemiología , Bases de Datos Factuales , Femenino , Humanos , Masculino , Registros Médicos , Persona de Mediana Edad , Miocarditis/epidemiología , Medición de Riesgo , Factores de Riesgo , Estados Unidos/epidemiología , Adulto Joven
3.
Artículo en Inglés | MEDLINE | ID: mdl-34547184

RESUMEN

Alectinib is an anaplastic lymphoma kinase (ALK) inhibitor approved for treatment of ALK-positive non-small cell lung cancer. Population pharmacokinetic (PK) models were developed for alectinib and its major active metabolite M4 using phase I/II PK data in crizotinib-failed patients (N = 138). The PK profiles were best described by two separate models with similar structure for both entities: open one-compartment models with sequential zero/first-order input and first-order elimination rate. Body weight with fixed allometric scaling factor on clearance and volume of both entities was the only significant covariate. Bayesian feedback analyses of the PK data collected from Japanese and global treatment-naïve patients in phase III studies (N = 334) confirmed the body weight effect. Landmark Cox proportional hazards analyses of progression-free survival in treatment-naïve patients identified the average molar concentrations of both entities alectinib and M4 during the first 6 weeks of treatment as a significant covariate, with an optimal response achieved for concentrations above 1040 nmol/L. With 600 mg twice daily (b.i.d.), 92% of global patients are above this threshold concentration, compared with only 43% of patients with 300 mg b.i.d. In Japan, where the body weight distribution is lower, the approved 300 mg b.i.d. dose brings about 70% of Japanese patients above this threshold. Logistic regression analyses found no significant relationship between the combined alectinib-M4 molar concentration and first occurrence of adverse events. These pharmacometric results were used to expedite and facilitate regulatory approvals of 600 mg b.i.d. for first-line ALK-positive NSCLC in the United States and European Union in 2017 and in China in 2018.

4.
Disaster Med Public Health Prep ; : 1-6, 2021 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-33557998

RESUMEN

Following hurricanes, there can be increases in exacerbations of chronic diseases, such as asthma. Asthma is common among children, and many asthma exacerbations can be prevented. This systematic literature review assessed literature describing the impact of hurricanes on children with asthma in the United States. Medline, Embase, Global Health, PubMed, and Scopus databases were searched for peer-reviewed, English-language articles published January 1990 to June 2019 that described the effect of a hurricane on children with asthma. This search identified 212 articles; 8 met inclusion criteria. All 8 were related to Hurricane Katrina, but research questions and study design varied. Articles included information on asthma after hurricanes from cross-sectional surveys, retrospective chart review, and objective clinical testing. Four articles described discontinuity in health insurance, asthma-related health care, or asthma medication use; and 3 articles examined the relationship between mold exposure and asthma symptoms and reported varying results. The eighth study quantified the burden of asthma among people visiting mobile medical units but did not describe factors associated with asthma symptoms. These results highlight opportunities for future research (eg, on more recent hurricanes) and disaster preparedness planning (eg, strategies to prevent health-care discontinuity among children with asthma).

5.
Rheumatology (Oxford) ; 60(10): 4568-4580, 2021 Oct 02.
Artículo en Inglés | MEDLINE | ID: mdl-33506875

RESUMEN

OBJECTIVES: To determine s.c. tocilizumab (s.c.-TCZ) dosing regimens for systemic JIA (sJIA) and polyarticular JIA (pJIA). METHODS: In two 52-week phase 1 b trials, s.c.-TCZ (162 mg/dose) was administered to sJIA patients every week or every 2 weeks (every 10 days before interim analysis) and to pJIA patients every 2 weeks or every 3 weeks with body weight ≥30 kg or <30 kg, respectively. Primary end points were pharmacokinetics, pharmacodynamics and safety; efficacy was exploratory. Comparisons were made to data from phase 3 trials with i.v. tocilizumab (i.v.-TCZ) in sJIA and pJIA. RESULTS: Study participants were 51 sJIA patients and 52 pJIA patients aged 1-17 years who received s.c.-TCZ. Steady-state minimum TCZ concentration (Ctrough) >5th percentile of that achieved with i.v.-TCZ was achieved by 49 (96%) sJIA and 52 (100%) pJIA patients. In both populations, pharmacodynamic markers of disease were similar between body weight groups. Improvements in Juvenile Arthritis DAS-71 were comparable between s.c.-TCZ and i.v.-TCZ. By week 52, 53% of sJIA patients and 31% of pJIA patients achieved clinical remission on treatment. Safety was consistent with that of i.v.-TCZ except for injection site reactions, reported by 41.2% and 28.8% of sJIA and pJIA patients, respectively. Infections were reported in 78.4% and 69.2% of patients, respectively. Two sJIA patients died; both deaths were considered to be related to TCZ. CONCLUSION: s.c.-TCZ provides exposure and risk/benefit profiles similar to those of i.v.-TCZ. S.c. administration provides an alternative administration route that is more convenient for patients and caregivers and that has potential for in-home use. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT01904292 and NCT01904279.

7.
J Asthma ; 58(3): 360-369, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-31755329

RESUMEN

OBJECTIVE: Priorities of the Centers for Disease Control and Prevention's 6|18 Initiative include outpatient asthma self-management education (ASME) and home-based asthma visits (home visit) as interventions for children with poorly-controlled asthma. ASME and home visit intervention programs are currently not widely available. This project was to assess the economic sustainability of these programs for state asthma control programs reimbursed by Medicaid. METHODS: We used a simulation model based on parameters from the literature and Medicaid claims, controlling for regression to the mean. We modeled scenarios under various selection criteria based on healthcare utilization and age to forecast the return on investment (ROI) using data from New York. The resulting tool is available in Excel or Python. RESULTS: Our model projected health improvement and cost savings for all simulated interventions. Compared against home visits alone, the simulated ASME alone intervention had a higher ROI for all healthcare utilization and age scenarios. Savings were primarily highest in simulated program participants who had two or more asthma-related emergency department visits or one inpatient visit compared to those participants who had one or more asthma-related emergency department visits. Segmenting the selection criteria by age did not significantly change the results. CONCLUSIONS: This model forecasts reduced healthcare costs and improved health outcomes as a result of ASME and home visits for children with high urgent healthcare utilization (more than two emergency department visits or one inpatient hospitalization) for asthma. Utilizing specific selection criteria, state based asthma control programs can improve health and reduce healthcare costs.

8.
Mol Ther ; 29(2): 555-570, 2021 02 03.
Artículo en Inglés | MEDLINE | ID: mdl-33038322

RESUMEN

Tremendous innovation is underway among a rapidly expanding repertoire of promising personalized immune-based treatments. Therapeutic cancer vaccines (TCVs) are attractive systemic immunotherapies that activate and expand antigen-specific CD8+ and CD4+ T cells to enhance anti-tumor immunity. Our review highlights key issues impacting TCVs in clinical practice and reports on progress in development. We review the mechanism of action, immune-monitoring, dosing strategies, combinations, obstacles, and regulation of cancer vaccines. Most trials of personalized TCVs are ongoing and represent diverse platforms with predominantly early investigations of mRNA, DNA, or peptide-based targeting strategies against neoantigens in solid tumors, with many in combination immunotherapies. Multiple delivery systems, routes of administration, and dosing strategies are used. Intravenous or intramuscular administration is common, including delivery by lipid nanoparticles. Absorption and biodistribution impact antigen uptake, expression, and presentation, affecting the strength, speed, and duration of immune response. The emerging trials illustrate the complexity of developing this class of innovative immunotherapies. Methodical testing of the multiple potential factors influencing immune responses, as well as refined quantitative methodologies to facilitate optimal dosing strategies, could help resolve uncertainty of therapeutic approaches. To increase the likelihood of success in bringing these medicines to patients, several unique development challenges must be overcome.

9.
J Asthma ; : 1-10, 2020 Aug 08.
Artículo en Inglés | MEDLINE | ID: mdl-32730723

RESUMEN

OBJECTIVE: To examine Medicaid expansion (ME) effects on health insurance coverage (HIC) and cost barriers to medical care among people with asthma. METHOD: We analyzed 2012-2013 and 2015-2016 data from low-income adults with current asthma aged 18-64 years in the Behavioral Risk Factor Surveillance System Asthma Call-Back Survey (state-level telephone survey). We calculated weighted percentages and 95% confidence intervals from ME and non-ME jurisdictions (according to 2014 ME status). Outcomes were HIC and cost barriers to buying asthma medication (MED), seeing a health care provider for asthma (HCP), or any asthma care (AAC). Using SUDAAN, we performed survey-weighted difference-in-differences analyses, adjusting for demographics. Subgroup analyses were stratified by demographics. RESULTS: Our study population included 6445 participants from 25 states plus Puerto Rico. In 2015-2016 compared to 2012-2013, HIC was more common in ME jurisdictions (P < 0.001) but unchanged in non-ME jurisdictions. Adjusted difference-in-differences analyses showed ME was associated with a statistically significant 13.36 percentage-point increase in HIC (standard error = 0.053). Cost barriers to MED, HCP, and AAC did not change significantly for either group in descriptive and difference-in-differences analyses. In subgroup analyses, we noted variation in outcomes by demographics and 2014 ME status. CONCLUSIONS: We found ME significantly affected HIC among low-income adults with asthma, but not cost barriers to asthma-related health care. Strategies to reduce cost barriers to asthma care could further improve health care access among low-income adults with asthma in ME jurisdictions.

10.
J Asthma ; : 1-7, 2020 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-32312135

RESUMEN

Objective: To examine the association between daycare attendance and asthma control among children aged 0 to 4 years with asthmaMethods: We analyzed 2012-2014 data from the Behavioral Risk Factor Surveillance System Asthma Call-back Survey on 388 children with asthma aged 0 to 4 years with information on daycare attendance in the past 12 months. We calculated weighted prevalence ratios to assess the association between daycare attendance and asthma control (categorized based on day-time and nighttime asthma symptoms, activity limitation, and short-acting beta agonist use). Adjusted models controlled for parent or guardian education, household income, race, sex, cost barriers to asthma care, long-term control medication use, and the number of other children in the child's household.Results: In this sample of children with asthma, representative of 520,400 children in 26 U.S. states, 34% attended daycare in the past 12 months. Only 32% of children who attended daycare in the past 12 months reported having an asthma action plan on file at the daycare they most recently attended. Presence of the asthma triggers of pets, mold, and smoking in a child's daycare were reported to be uncommon. Prevalence of uncontrolled asthma was 44% in children who attended daycare in the past 12 months and 68% in children who did not. The adjusted prevalence ratio between daycare attendance and uncontrolled asthma was 0.96 (95% confidence interval 0.73, 1.25).Conclusions: When adjusting for covariates, we observed no evidence of an association between daycare attendance in early life and uncontrolled asthma.

12.
Pediatr Rheumatol Online J ; 17(1): 57, 2019 Aug 22.
Artículo en Inglés | MEDLINE | ID: mdl-31438986

RESUMEN

BACKGROUND: The anti-interleukin-6 receptor-alpha antibody tocilizumab was approved for intravenous (IV) injection in the treatment of patients with systemic juvenile idiopathic arthritis (sJIA) aged 2 to 17 years based on results of a randomized controlled phase 3 trial. Tocilizumab treatment in systemic juvenile idiopathic arthritis (sJIA) patients younger than 2 was investigated in this open-label phase 1 trial and compared with data from the previous trial in patients aged 2 to 17 years. METHODS: Patients younger than 2 received open-label tocilizumab 12 mg/kg IV every 2 weeks (Q2W) during a 12-week main evaluation period and an optional extension period. The primary end point was comparability of pharmacokinetics during the main evaluation period to that of the previous trial (in patients aged 2-17 years), and the secondary end point was safety; pharmacodynamics and efficacy end points were exploratory. Descriptive comparisons for pharmacokinetics, pharmacodynamics, safety, and efficacy were made with sJIA patients aged 2 to 17 years weighing < 30 kg (n = 38) who received tocilizumab 12 mg/kg IV Q2W in the previous trial (control group). RESULTS: Eleven patients (mean age, 1.3 years) received tocilizumab during the main evaluation period. The primary end point was met: tocilizumab exposures for patients younger than 2 were within the range of the control group (mean [±SD] µg/mL concentration at the end-of-dosing interval [Cmin]: 39.8 [±14.3] vs 57.5 [±23.3]; maximum concentration [Cmax] postdose: 288 [±40.4] vs 245 [±57.2]). At week 12, pharmacodynamic measures were similar between patients younger than 2 and the control group; mean change from baseline in Juvenile Arthritis Disease Activity Score-71 was - 17.4 in patients younger than 2 and - 28.8 in the control group; rash was reported by 14.3 and 13.5% of patients, respectively. Safety was comparable except for the incidence of serious hypersensitivity reactions (27.3% in patients younger than 2 vs 2.6% in the control group). CONCLUSIONS: Tocilizumab 12 mg/kg IV Q2W provided pharmacokinetics, pharmacodynamics, and efficacy in sJIA patients younger than 2 comparable to those in patients aged 2 to 17 years. Safety was comparable except for a higher incidence of serious hypersensitivity events in patients younger than 2 years. CLASSIFICATION: Juvenile idiopathic arthritis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01455701 . Registered, October 20, 2011, Date of enrollment of first participant: October 26, 2012.


Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Juvenil/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/farmacocinética , Antirreumáticos/efectos adversos , Antirreumáticos/farmacocinética , Esquema de Medicación , Hipersensibilidad a las Drogas/etiología , Femenino , Humanos , Lactante , Masculino , Resultado del Tratamiento
13.
Immunity ; 50(6): 1381-1390.e5, 2019 06 18.
Artículo en Inglés | MEDLINE | ID: mdl-31103381

RESUMEN

The process of affinity maturation, whereby T and B cells bearing antigen receptors with optimal affinity to the relevant antigen undergo preferential expansion, is a key feature of adaptive immunity. Natural killer (NK) cells are innate lymphocytes capable of "adaptive" responses after cytomegalovirus (CMV) infection. However, whether NK cells are similarly selected on the basis of their avidity for cognate ligand is unknown. Here, we showed that NK cells with the highest avidity for the mouse CMV glycoprotein m157 were preferentially selected to expand and comprise the memory NK cell pool, whereas low-avidity NK cells possessed greater capacity for interferon-γ (IFN-γ) production. Moreover, we provide evidence for avidity selection occurring in human NK cells during human CMV infection. These results delineate how heterogeneity in NK cell avidity diversifies NK cell effector function during antiviral immunity, and how avidity selection might serve to produce the most potent memory NK cells.


Asunto(s)
Infecciones por Citomegalovirus/inmunología , Infecciones por Citomegalovirus/virología , Citomegalovirus/inmunología , Interacciones Huésped-Patógeno/inmunología , Células Asesinas Naturales/inmunología , Animales , Infecciones por Citomegalovirus/metabolismo , Citotoxicidad Inmunológica , Regulación de la Expresión Génica , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/metabolismo , Infecciones por Herpesviridae/virología , Interacciones Huésped-Patógeno/genética , Humanos , Memoria Inmunológica , Células Asesinas Naturales/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Noqueados , Muromegalovirus/inmunología , Subfamilia A de Receptores Similares a Lectina de Células NK/genética , Subfamilia A de Receptores Similares a Lectina de Células NK/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T
14.
Prev Med Rep ; 14: 100860, 2019 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-30989035

RESUMEN

Short-term exposure to air pollution can result in acute health effects, particularly for individuals with respiratory and cardiovascular disease. Air quality alert programs that notify the public about high air pollution days are critical for susceptible populations. We assessed how U.S. adults receive air quality alerts and whether it varies by demographic or health characteristics. We analyzed data from the summer 2014 wave of ConsumerStyles, a nationally representative survey of U.S. adults (n = 4269). We calculated the weighted proportion of individuals who received air quality alerts from seven communication channels, combining all individuals and stratifying by demographics. To assess whether the reach of communication channels varied by respiratory and cardiovascular disease status, we computed weighted prevalence ratios adjusted for sex, age, race, and education. Forty-eight percent of U.S. adults had heard about air quality alerts. Within every demographic category, television was the most common communication channel (76% among individuals aware of air quality alerts). Other common communication modes were radio (30%), newspaper (24%), and internet (20%). Less common communication modes were friend or family member, mobile phone or device app, and electronic highway sign. The reach of communication channels varied by demographic factors, such as age, but not by respiratory or cardiovascular disease status. Television is the most common communication channel for receiving air quality alerts. Expanding use of other communication channels might increase awareness of air quality alerts. These results can help decision-makers target communication channels that reach susceptible populations and will achieve the greatest impact.

16.
Prev Chronic Dis ; 15: E110, 2018 09 06.
Artículo en Inglés | MEDLINE | ID: mdl-30191809

RESUMEN

Asthma affects more than 24 million Americans, including 6.2 million children. Although asthma cannot be cured, it can be effectively managed with care based on nationally recognized guidelines. Ensuring the availability and accessibility of guidelines-recommended treatments and services can help patients receive the most appropriate care. In this article, we describe the American Lung Association's Asthma Guidelines-Based Care Coverage Project (the Project) to determine the extent of asthma care coverage and associated barriers in state Medicaid programs - information that has been previously unavailable. The Project tracked coverage for 7 areas of guidelines-based asthma care and 9 barriers related to accessing care in Medicaid programs for all 50 states, the District of Columbia, and Puerto Rico. Results from the Project show a lack of consistent and comprehensive coverage across states, as well as coverage-related challenges to accessing asthma care within states.


Asunto(s)
Asma/economía , Cobertura del Seguro/estadística & datos numéricos , Medicaid/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Adolescente , Adulto , Asma/terapia , Niño , Costo de Enfermedad , District of Columbia , Femenino , Accesibilidad a los Servicios de Salud , Humanos , Masculino , Medicaid/economía , Persona de Mediana Edad , Puerto Rico , Estados Unidos , Adulto Joven
17.
J Clin Invest ; 128(10): 4654-4668, 2018 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-30198904

RESUMEN

Checkpoint blockade immunotherapy targeting the PD-1/PD-L1 inhibitory axis has produced remarkable results in the treatment of several types of cancer. Whereas cytotoxic T cells are known to provide important antitumor effects during checkpoint blockade, certain cancers with low MHC expression are responsive to therapy, suggesting that other immune cell types may also play a role. Here, we employed several mouse models of cancer to investigate the effect of PD-1/PD-L1 blockade on NK cells, a population of cytotoxic innate lymphocytes that also mediate antitumor immunity. We discovered that PD-1 and PD-L1 blockade elicited a strong NK cell response that was indispensable for the full therapeutic effect of immunotherapy. PD-1 was expressed on NK cells within transplantable, spontaneous, and genetically induced mouse tumor models, and PD-L1 expression in cancer cells resulted in reduced NK cell responses and generation of more aggressive tumors in vivo. PD-1 expression was more abundant on NK cells with an activated and more responsive phenotype and did not mark NK cells with an exhausted phenotype. These results demonstrate the importance of the PD-1/PD-L1 axis in inhibiting NK cell responses in vivo and reveal that NK cells, in addition to T cells, mediate the effect of PD-1/PD-L1 blockade immunotherapy.


Asunto(s)
Antígeno B7-H1/inmunología , Inmunoterapia , Células Asesinas Naturales/inmunología , Neoplasias Experimentales/terapia , Receptor de Muerte Celular Programada 1/inmunología , Animales , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/genética , Humanos , Células K562 , Células Asesinas Naturales/patología , Ratones , Ratones Noqueados , Neoplasias Experimentales/genética , Neoplasias Experimentales/patología , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética
18.
Nat Med ; 24(8): 1178-1191, 2018 08.
Artículo en Inglés | MEDLINE | ID: mdl-29942093

RESUMEN

Intratumoral stimulatory dendritic cells (SDCs) play an important role in stimulating cytotoxic T cells and driving immune responses against cancer. Understanding the mechanisms that regulate their abundance in the tumor microenvironment (TME) could unveil new therapeutic opportunities. We find that in human melanoma, SDC abundance is associated with intratumoral expression of the gene encoding the cytokine FLT3LG. FLT3LG is predominantly produced by lymphocytes, notably natural killer (NK) cells in mouse and human tumors. NK cells stably form conjugates with SDCs in the mouse TME, and genetic and cellular ablation of NK cells in mice demonstrates their importance in positively regulating SDC abundance in tumor through production of FLT3L. Although anti-PD-1 'checkpoint' immunotherapy for cancer largely targets T cells, we find that NK cell frequency correlates with protective SDCs in human cancers, with patient responsiveness to anti-PD-1 immunotherapy, and with increased overall survival. Our studies reveal that innate immune SDCs and NK cells cluster together as an excellent prognostic tool for T cell-directed immunotherapy and that these innate cells are necessary for enhanced T cell tumor responses, suggesting this axis as a target for new therapies.


Asunto(s)
Células Dendríticas/inmunología , Inmunoterapia , Células Asesinas Naturales/inmunología , Microambiente Tumoral/inmunología , Antígenos de Superficie/metabolismo , Comunicación Celular , Supervivencia Celular , Humanos , Linfocitos/metabolismo , Melanoma/inmunología , Melanoma/patología , Proteínas de la Membrana/metabolismo , Análisis de Supervivencia
19.
Cancer Chemother Pharmacol ; 82(1): 129-138, 2018 07.
Artículo en Inglés | MEDLINE | ID: mdl-29748847

RESUMEN

PURPOSE: Alectinib is a selective and potent anaplastic lymphoma kinase (ALK) inhibitor that is active in the central nervous system (CNS). Alectinib demonstrated robust efficacy in a pooled analysis of two single-arm, open-label phase II studies (NP28673, NCT01801111; NP28761, NCT01871805) in crizotinib-resistant ALK-positive non-small-cell lung cancer (NSCLC): median overall survival (OS) 29.1 months (95% confidence interval [CI]: 21.3-39.0) for alectinib 600 mg twice daily (BID). We investigated exposure-response relationships from final pooled phase II OS and safety data to assess alectinib dose selection. METHODS: A semi-parametric Cox proportional hazards model analyzed relationships between individual median observed steady-state trough concentrations (Ctrough,ss) for combined exposure of alectinib and its major metabolite (M4), baseline covariates (demographics and disease characteristics) and OS. Univariate logistic regression analysis analyzed relationships between Ctrough,ss and incidence of adverse events (AEs: serious and Grade ≥ 3). RESULTS: Overall, 92% of patients (n = 207/225) had Ctrough,ss data and were included in the analysis. No statistically significant relationship was found between Ctrough,ss and OS following alectinib treatment. The only baseline covariates that statistically influenced OS were baseline tumor size and prior crizotinib treatment duration. Larger baseline tumor size and shorter prior crizotinib treatment were both associated with shorter OS. Logistic regression confirmed no significant relationship between Ctrough,ss and AEs. CONCLUSION: Alectinib 600 mg BID provides systemic exposures at plateau of response for OS while maintaining a well-tolerated safety profile. This analysis confirms alectinib 600 mg BID as the recommended global dose for patients with crizotinib-resistant ALK-positive NSCLC.


Asunto(s)
Carbazoles/administración & dosificación , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Crizotinib/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Piperidinas/administración & dosificación , Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Quinasa de Linfoma Anaplásico/biosíntesis , Quinasa de Linfoma Anaplásico/genética , Carbazoles/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/enzimología , Carcinoma de Pulmón de Células no Pequeñas/genética , Ensayos Clínicos Fase II como Asunto , Relación Dosis-Respuesta a Droga , Resistencia a Antineoplásicos , Femenino , Reordenamiento Génico , Humanos , Estimación de Kaplan-Meier , Neoplasias Pulmonares/enzimología , Neoplasias Pulmonares/genética , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Piperidinas/efectos adversos , Modelos de Riesgos Proporcionales , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/efectos adversos
20.
J Allergy Clin Immunol Pract ; 6(1): 236-243.e7, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-28756082

RESUMEN

BACKGROUND: Asthma morbidity is increased among older adults, especially older adult women. Interventions to improve asthma control in this population are not well described. OBJECTIVE: The objective of this study was to identify risk factors (including modifiable factors) associated with asthma-related hospitalizations and emergency department or urgent care center visits (ED/UCV) among older adults. A secondary objective was to investigate sex differences in variables relevant to asthma control. METHODS: Data were obtained from 14,076 older adults ≥65 years with active asthma participating in the 2006-2010 Behavioral Risk Factor Surveillance System Asthma Call-back Survey (a random-digit dialed survey) in 40 US states, the District of Columbia, and Puerto Rico, representative of >2.6 million persons. Weighted, adjusted logistic regression was conducted. RESULTS: One or more asthma-related hospitalizations in the past year were reported by 5.7% (95% confidence interval [95% CI] = 5.0% to 6.4%) of participants; 10.6% (95% CI = 9.7% to 11.5%) reported ≥1 asthma-related ED/UCV. Compared with older adults without asthma-related hospitalizations, adjusted odds were higher among those with ≥1 asthma-related hospitalization for chronic obstructive pulmonary disease (COPD), coronary artery disease, depression, cockroaches or mold in the home, and cost barriers to asthma-related health care or medication. All these factors, except for cockroaches, were associated with asthma-related ED/UCV. Compared with males, adjusted odds were higher among females for COPD, depression, obesity, and cost barriers to asthma-related health care or medication. CONCLUSIONS: Among older adults, asthma-related hospitalizations and ED/UCV were associated with clinical comorbidities, mold in the home, and financial barriers to asthma-related health care. Interventions addressing modifiable factors could reduce asthma morbidity among older adults.


Asunto(s)
Factores de Edad , Asma/epidemiología , Enfermedad de la Arteria Coronaria/epidemiología , Depresión/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Anciano , Anciano de 80 o más Años , Alérgenos/inmunología , Animales , Cucarachas/inmunología , Comorbilidad , Servicios Médicos de Urgencia/estadística & datos numéricos , Femenino , Hongos/inmunología , Accesibilidad a los Servicios de Salud , Hospitalización/estadística & datos numéricos , Humanos , Masculino , Morbilidad , Factores de Riesgo , Factores Sexuales , Estados Unidos/epidemiología
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