RESUMEN
Teclistamab is a Bcell maturation antigen (BCMA)-directed bispecific antibody approved for the treatment of patients with triple-class exposed relapsed/refractory multiple myeloma. In the phase 1/2 MajesTEC-1 study, a cohort of patients who had prior BCMA-targeted therapy (antibody-drug conjugate [ADC] or CAR-T cell therapy) were enrolled to explore teclistamab in patients previously exposed to anti-BCMA treatment. At median follow-up of 28.0 months (range, 0.7-31.1), 40 patients with prior BCMA-targeted therapy had received subcutaneous 1.5 mg/kg weekly teclistamab. Median prior lines of treatment were 6 (range, 3-14). Prior anti-BCMA therapy included ADC (n = 29), CAR-T (n = 15), or both (n = 4). Overall response rate was 52.5%; 47.5% of patients achieved very good partial response or better and 30.0% achieved complete response or better. Median duration of response was 14.8 months, median progression-free survival was 4.5 months, and median overall survival was 15.5 months. The most common treatment-emergent adverse events (TEAEs) were neutropenia, infections, cytokine release syndrome, and anemia; cytopenias and infections were the most common grade ≥3 TEAEs. Infections occurred in 28 (70.0%) patients (n = 13 [32.5%] maximum grade 3/4; n = 4 [10%] grade 5). Prior to starting teclistamab, baseline BCMA expression and immune characteristics were unaffected by prior anti-BCMA treatment. The MajesTEC-1 trial cohort C results demonstrate favorable efficacy and safety of teclistamab in patients with heavily pretreated RRMM and prior anti-BCMA treatment. NCT03145181; NCT04557098.
RESUMEN
ABSTRACT: Teclistamab, an off-the-shelf B-cell maturation antigen (BCMA) × CD3 bispecific antibody that mediates T-cell activation and subsequent lysis of BCMA-expressing myeloma cells, is approved for the treatment of patients with relapsed/refractory multiple myeloma (R/RMM). As a T-cell redirection therapy, clinical outcomes with teclistamab may be influenced by patient immune fitness and tumor antigen expression. We correlated tumor characteristics and baseline immune profiles with clinical response and disease burden in patients with R/RMM from the pivotal phase 1/2 MajesTEC-1 study, focusing on patients treated with 1.5 mg/kg of teclistamab (N = 165). Peripheral blood samples were collected at screening, and bone marrow samples were collected at screening and cycle 3. Better clinical outcomes to teclistamab correlated with higher baseline total T-cell counts in the periphery. In addition, responders (partial response or better) had a lower proportion of immunosuppressive regulatory T cells (Tregs), T cells expressing coinhibitory receptors (CD38, PD-1, and PD-1/TIM-3), and soluble BCMA and a T-cell profile suggestive of a more cytolytic potential, compared with nonresponders. Neither frequency of baseline bone marrow BCMA expression nor BCMA-receptor density was associated with clinical response to teclistamab. Improved progression-free survival was observed in patients with a lower frequency of T cells expressing exhaustion markers and immunosuppressive Tregs. Overall, response to teclistamab was associated with baseline immune fitness; nonresponders had immune profiles suggestive of immune suppression and T-cell dysfunction. These findings illustrate the importance of the contribution of the immune landscape to T-cell redirection therapy response. This trial was registered at www.ClinicalTrials.gov as #NCT03145181/NCT04557098.
Asunto(s)
Mieloma Múltiple , Humanos , Mieloma Múltiple/inmunología , Mieloma Múltiple/tratamiento farmacológico , Mieloma Múltiple/patología , Mieloma Múltiple/terapia , Masculino , Anticuerpos Biespecíficos/uso terapéutico , Femenino , Antígeno de Maduración de Linfocitos B/inmunología , Persona de Mediana Edad , AncianoRESUMEN
Malassezia are yeast species that commonly colonize healthy skin. However, they have been associated with or implicated in the pathogenesis of numerous skin disorders, particularly in the setting of pediatric populations. In this review, we will focus on several Malassezia-associated skin conditions manifesting in infants, children, and adolescents: pityriasis versicolor, Malassezia folliculitis, infantile and adolescent seborrheic dermatitis, head and neck dermatitis, and neonatal cephalic pustulosis. We examine the literature and provide an overview of these conditions, including clinical presentation in diverse skin colors, diagnosis, risk factors, and treatment and management. Additionally, we summarize and highlight some of the proposed theories on the role of Malassezia spp. in the pathogenesis of these skin conditions.
RESUMEN
Importance: The effects of breast cancer incidence changes and advances in screening and treatment on outcomes of different screening strategies are not well known. Objective: To estimate outcomes of various mammography screening strategies. Design, Setting, and Population: Comparison of outcomes using 6 Cancer Intervention and Surveillance Modeling Network (CISNET) models and national data on breast cancer incidence, mammography performance, treatment effects, and other-cause mortality in US women without previous cancer diagnoses. Exposures: Thirty-six screening strategies with varying start ages (40, 45, 50 years) and stop ages (74, 79 years) with digital mammography or digital breast tomosynthesis (DBT) annually, biennially, or a combination of intervals. Strategies were evaluated for all women and for Black women, assuming 100% screening adherence and "real-world" treatment. Main Outcomes and Measures: Estimated lifetime benefits (breast cancer deaths averted, percent reduction in breast cancer mortality, life-years gained), harms (false-positive recalls, benign biopsies, overdiagnosis), and number of mammograms per 1000 women. Results: Biennial screening with DBT starting at age 40, 45, or 50 years until age 74 years averted a median of 8.2, 7.5, or 6.7 breast cancer deaths per 1000 women screened, respectively, vs no screening. Biennial DBT screening at age 40 to 74 years (vs no screening) was associated with a 30.0% breast cancer mortality reduction, 1376 false-positive recalls, and 14 overdiagnosed cases per 1000 women screened. Digital mammography screening benefits were similar to those for DBT but had more false-positive recalls. Annual screening increased benefits but resulted in more false-positive recalls and overdiagnosed cases. Benefit-to-harm ratios of continuing screening until age 79 years were similar or superior to stopping at age 74. In all strategies, women with higher-than-average breast cancer risk, higher breast density, and lower comorbidity level experienced greater screening benefits than other groups. Annual screening of Black women from age 40 to 49 years with biennial screening thereafter reduced breast cancer mortality disparities while maintaining similar benefit-to-harm trade-offs as for all women. Conclusions: This modeling analysis suggests that biennial mammography screening starting at age 40 years reduces breast cancer mortality and increases life-years gained per mammogram. More intensive screening for women with greater risk of breast cancer diagnosis or death can maintain similar benefit-to-harm trade-offs and reduce mortality disparities.
Asunto(s)
Neoplasias de la Mama , Detección Precoz del Cáncer , Mamografía , Adulto , Anciano , Femenino , Humanos , Persona de Mediana Edad , Factores de Edad , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/diagnóstico por imagen , Técnicas de Apoyo para la Decisión , Reacciones Falso Positivas , Incidencia , Tamizaje Masivo , Uso Excesivo de los Servicios de Salud , Guías de Práctica Clínica como Asunto , Estados Unidos/epidemiología , Modelos EstadísticosRESUMEN
OBJECTIVES: Epidermal growth factor receptor (EGFR) inhibition with cetuximab is a standard treatment for head and neck squamous cell carcinoma (HNSCC). Activation of the receptor tyrosine kinases AXL, MET and VEGFR can mediate resistance to cetuximab. Cabozantinib, a multikinase inhibitor (MKI) targeting AXL/MET/VEGFR, has demonstrated antitumor activity in preclinical models of HNSCC. This investigator- initiated phase I trial evaluated the safety and efficacy of cetuximab plus cabozantinib in patients with recurrent/metastatic (R/M) HNSCC. MATERIALS AND METHODS: Patients received cetuximab concurrently with cabozantinib daily on a 28-day cycle. Using a 3 + 3 dose-escalation design, the primary endpoint was to determine the maximally tolerated dose (MTD) of cabozantinib. Secondary endpoints included overall response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) RESULTS: Among the 20 patients enrolled, most had prior disease progression on immune checkpoint inhibitors (95 %), platinum-based chemotherapy (95 %), and cetuximab (80 %). No dose-limiting toxicities were recorded and the MTD for cabozantinib was established to be 60 mg. Grade ≥ 3 adverse events occurred in 65 % of patients (n = 13). ORR was 20 %, with 4 partial responses (PRs). Two PRs were observed in cetuximab-naïve patients (n = 4), with an ORR of 50 % in this subgroup. In the overall population, DCR was 75 %, median PFS was 3.4 months and median OS was 8.1 months. CONCLUSION: Cetuximab plus cabozantinib demonstrated a manageable toxicity profile and preliminary efficacy in patients with heavily treated R/M HNSCC. The combination of cetuximab with MKIs targeting the AXL/MET/VEGFR axis warrants further investigation, including in cetuximab-naïve patients.
Asunto(s)
Anilidas , Protocolos de Quimioterapia Combinada Antineoplásica , Cetuximab , Piridinas , Carcinoma de Células Escamosas de Cabeza y Cuello , Humanos , Anilidas/uso terapéutico , Anilidas/administración & dosificación , Masculino , Cetuximab/uso terapéutico , Cetuximab/administración & dosificación , Piridinas/uso terapéutico , Piridinas/administración & dosificación , Femenino , Persona de Mediana Edad , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Adulto , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/patología , Metástasis de la NeoplasiaRESUMEN
Importance: Chronic skin disorders in children frequently are visible and can cause stigmatization. However, the extent of stigmatization from chronic skin disease and association with mental health needs further study. Objective: To examine the extent of stigma, dependence on disease visibility and severity, and association with mental health and quality of life (QOL) in chronic pediatric skin disease. Design, Setting, and Participants: A cross-sectional, single-visit study was conducted at 32 pediatric dermatology centers in the US and Canada from November 14, 2018, to November 17, 2021. Participants included patients aged 8 to 17 years with chronic skin disease and 1 parent. Main Outcomes and Measures: Using the Patient-Reported Outcomes Measurement Instrumentation System (PROMIS) Stigma-Skin, the extent of stigma with child-, caregiver-, and physician-assessed disease visibility (primary outcome) and severity was compared, as well as reduced QOL (assessed by Skindex-Teen), depression, anxiety, and poor peer relationships (PROMIS child and proxy tools) (secondary outcomes). Results: The study included 1671 children (57.9% female; mean [SD] age, 13.7 [2.7] years). A total of 56.4% participants had self-reported high disease visibility and 50.5% had moderate disease severity. Stigma scores significantly differed by level of physician-assessed and child/proxy-assessed disease visibility and severity. Among children with chronic skin disorders, predominantly acne, atopic dermatitis, alopecia areata, and vitiligo, only 27.0% had T scores less than 40 (minimal or no stigma) and 43.8% had at least moderate stigma (T score ≥45) compared with children with a range of chronic diseases. Stigma scores correlated strongly with reduced QOL (Spearman ρ = 0.73), depression (ρ = 0.61), anxiety (ρ = 0.54), and poor peer relationships (ρ = -0.49). Overall, 29.4% of parents were aware of bullying of their child, which was strongly associated with stigma (Cohen d = -0.79, with children who were not bullied experiencing lower levels of stigma). Girls reported more stigma than boys (Cohen d = 0.26). Children with hyperhidrosis and hidradenitis suppurativa were most likely to have increased depression and anxiety. Conclusions and Relevance: The findings of this study suggest that physician assessment of disease severity and visibility is insufficient to evaluate the disease impact in the patient/caregiver. Identifying stigmatization, including bullying, and tracking improvement through medical and psychosocial interventions may be a key role for practitioners.
Asunto(s)
Salud Mental , Calidad de Vida , Enfermedades de la Piel , Estigma Social , Humanos , Femenino , Masculino , Niño , Adolescente , Estudios Transversales , Enfermedades de la Piel/psicología , Enfermedad Crónica , Canadá , Estereotipo , Índice de Severidad de la Enfermedad , Depresión/epidemiología , Depresión/psicología , Depresión/etiología , Estados Unidos , Ansiedad/psicología , Ansiedad/epidemiología , Ansiedad/etiología , Medición de Resultados Informados por el PacienteRESUMEN
A investigação teve como objetivo conhecer os nexos e desafios entre a formação e a práxis profissional e as recomendações das Diretrizes Curriculares Nacionais do Curso de Graduação em Enfermagem. Estudo qualitativo, com 34 diplomados em Enfermagem, que responderam ao questionário por e-mail. A análise dos dados foi baseada na análise de discurso de Michael Foucault. Os aspectos éticos foram respeitados. A análise apontou três temáticas nos discursos dos diplomados - Sistema Único de Saúde, formação generalista e humanização. O estudo revelou uma aproximação das concepções e orientações das Diretrizes Curriculares e do SUS com a realidade da práxis profissional, bem como desafios para a formação do enfermeiro.
The objective of the study was to know the linkages and challenges between professional training and practice and the Curriculum Guidelines for Nursing Baccalaureate Degree Programs. It was a qualitative study, with 34 graduates in nursing, who answered an e-mailed questionnaire. Data analysis was based on Michael Foucault's discourse analysis. The ethical aspects were observed. Analysis showed three themes in graduates discourses - Unified Health System, generalist professional training and humanization. The study revealed an approximation of concepts and guidelines of the Curriculum Guidelines for Nursing Baccalaureate Degree Programs and of the Unified Health System with the reality of professional practice along with challenges in the training of professional nurses.
La investigación tuve como objetivo conocer los vínculos y desafíos entre la formación y práctica profesional y las recomendaciones de las Directrices Curriculares Nacionales del curso de pregrado de enfermería. Estudio cualitativo, con 34 licenciados en enfermería, que respondieron al cuestionario por correo electrónico. El análisis de los datos ha sido basada en la análisis de discurso de Michael Foucault. Los aspectos éticos se observaron. El análisis identifica tres temas en los discursos de los graduados Sistema Único de Salud, la formación generalista y humanización. El estudio reveló una aproximación de conceptos y recomendaciones de las Directrices Curriculares Nacionales y del Sistema Único de Salud con la realidad de la práctica profesional, así como los retos para la formación de enfermeras.
Asunto(s)
Educación en Enfermería/normas , CurriculumRESUMEN
O presente projeto de intervenção em serviço propõe a implantação de acolhimento com classificação de risco (ACCR) no Centro Obstétrico (CO) do Hospital São Lucas da PUCRS. A superlotação dos serviços de emergência nos hospitais, o acesso por ordem de chegada e a qualidade da assistência prestada têm trazido crescente preocupação a médicos, administradores e gestores e, mais ainda, tem sido motivo de insatisfação a usuários e trabalhadores de saúde. Tendo em vista que o CO vivencia dificuldades deste tipo, este projeto tem por objetivo reorganizar o processo de trabalho, baseando-se em princípios éticos, humanísticos e técnicos, aperfeiçoando o acesso, acolhendo as usuárias no que a tange a postura do profissional em escutar a sua demanda e priorizando o atendimento conforme o risco. A proposta visa abranger todas as gestantes, parturientes e puerperas que buscarem atendimento no CO do HSL, proporcionando assistência humanizada, pautada em protocolos, resolutiva e preocupada com a continuidade do atendimento. Os resultados, portanto, devem refletir na agilidade de atendimento com redução dos tempos de espera, humanização das relações trabalhadores-usuários, integração de diferentes categorias profissionais no processo e qualificação da assistência, aumentando o grau de satisfação tanto das usuárias quanto dos profissionais de saúde envolvidos.