RESUMEN
BACKGROUND: 'Stable disease (SD)' as per RECIST is a common but ambiguous outcome in patients receiving immune checkpoint inhibitors (ICIs). This study aimed to characterize SD and identify the subset of patients with SD who are benefiting from treatment. Understanding SD would facilitate drug development and improve precision in correlative research. PATIENTS AND METHODS: A systematic review was carried out to characterize SD in ICI trials. SD and objective response were compared to proliferation index using The Cancer Genome Atlas gene expression data. To identify a subgroup of SD with outcomes mirroring responders, we examined a discovery cohort of non-small-cell lung cancer (NSCLC). Serial cutpoints of two variables, % best overall response and progression-free survival (PFS), were tested to define a subgroup of patients with SD with similar survival as responders. Results were then tested in external validation cohorts. RESULTS: Among trials of ICIs (59 studies, 14 280 patients), SD ranged from 16% to 42% in different tumor types and was associated with disease-specific proliferation index (ρ = -0.75, P = 0.03), a proxy of tumor kinetics, rather than relative response to ICIs. In a discovery cohort of NSCLC [1220 patients, 313 (26%) with SD to ICIs], PFS ranged widely in SD (0.2-49 months, median 4.9 months). The subset with PFS >6 months and no tumor growth mirrored partial response (PR) minor (overall survival hazard ratio 1.0) and was proposed as the definition of SD responder. This definition was confirmed in two validation cohorts from trials of NSCLC treated with durvalumab and found to apply in tumor types treated with immunotherapy in which depth and duration of benefit were correlated. CONCLUSIONS: RECIST-defined SD to immunotherapy is common, heterogeneous, and may largely reflect tumor growth rate rather than ICI response. In patients with NSCLC and SD to ICIs, PFS >6 months and no tumor growth may be considered 'SD responders'. This definition may improve the efficiency of and insight derivable from clinical and translational research.
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Antineoplásicos Inmunológicos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologíaRESUMEN
BACKGROUND: Patients with lung cancers may have disproportionately severe coronavirus disease 2019 (COVID-19) outcomes. Understanding the patient-specific and cancer-specific features that impact the severity of COVID-19 may inform optimal cancer care during this pandemic. PATIENTS AND METHODS: We examined consecutive patients with lung cancer and confirmed diagnosis of COVID-19 (n = 102) at a single center from 12 March 2020 to 6 May 2020. Thresholds of severity were defined a priori as hospitalization, intensive care unit/intubation/do not intubate ([ICU/intubation/DNI] a composite metric of severe disease), or death. Recovery was defined as >14 days from COVID-19 test and >3 days since symptom resolution. Human leukocyte antigen (HLA) alleles were inferred from MSK-IMPACT (n = 46) and compared with controls with lung cancer and no known non-COVID-19 (n = 5166). RESULTS: COVID-19 was severe in patients with lung cancer (62% hospitalized, 25% died). Although severe, COVID-19 accounted for a minority of overall lung cancer deaths during the pandemic (11% overall). Determinants of COVID-19 severity were largely patient-specific features, including smoking status and chronic obstructive pulmonary disease [odds ratio for severe COVID-19 2.9, 95% confidence interval 1.07-9.44 comparing the median (23.5 pack-years) to never-smoker and 3.87, 95% confidence interval 1.35-9.68, respectively]. Cancer-specific features, including prior thoracic surgery/radiation and recent systemic therapies did not impact severity. Human leukocyte antigen supertypes were generally similar in mild or severe cases of COVID-19 compared with non-COVID-19 controls. Most patients recovered from COVID-19, including 25% patients initially requiring intubation. Among hospitalized patients, hydroxychloroquine did not improve COVID-19 outcomes. CONCLUSION: COVID-19 is associated with high burden of severity in patients with lung cancer. Patient-specific features, rather than cancer-specific features or treatments, are the greatest determinants of severity.
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Betacoronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Neoplasias Pulmonares/epidemiología , Neoplasias Pulmonares/terapia , Neumonía Viral/epidemiología , Neumonía Viral/terapia , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/inmunología , Antígeno B7-H1/uso terapéutico , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Femenino , Estudios de Seguimiento , Hospitalización/tendencias , Humanos , Hidroxicloroquina/uso terapéutico , Neoplasias Pulmonares/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , Estudios Retrospectivos , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
BACKGROUND: Programmed death-ligand 1 (PD-L1) expression is the only FDA-approved biomarker for immune checkpoint inhibitors (ICIs) in patients with lung adenocarcinoma, but sensitivity is modest. Understanding the impact of molecular phenotype, clinical characteristics, and tumor features on PD-L1 expression is largely unknown and may improve prediction of response to ICI. PATIENTS AND METHODS: We evaluated patients with lung adenocarcinoma for whom PD-L1 testing and targeted next-generation sequencing (using MSK-IMPACT) was performed on the same tissue sample. Clinical and molecular features were compared across PD-L1 subgroups to examine how molecular phenotype associated with tumor PD-L1 expression. In patients treated with anti-PD-(L)1 blockade, we assessed how these interactions impacted efficacy. RESULTS: A total of 1586 patients with lung adenocarcinoma had paired PD-L1 testing and targeted next-generation sequencing. PD-L1 negativity was more common in primary compared to metastatic samples (P < 0.001). The distribution of PD-L1 expression (lymph nodes enriched for PD-L1 high; bones predominantly PD-L1 negative) and predictiveness of PD-L1 expression on ICI response varied by organ. Mutations in KRAS, TP53, and MET significantly associated with PD-L1 high expression (each P < 0.001, Q < 0.001) and EGFR and STK11 mutations associated with PD-L1 negativity (P < 0.001, Q = 0.01; P = 0.001, Q < 0.001, respectively). WNT pathway alterations also associated with PD-L1 negativity (P = 0.005). EGFR and STK11 mutants abrogated the predictive value of PD-L1 expression on ICI response. CONCLUSION: PD-L1 expression and association with ICI response vary across tissue sample sites. Specific molecular features are associated with differential expression of PD-L1 and may impact the predictive capacity of PD-L1 for response to ICIs.
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Antígeno B7-H1 , Neoplasias Pulmonares , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/genética , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , MutaciónRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) are standard therapies for patients with advanced non-small-cell lung cancer (NSCLC) and a programmed death-ligand 1 (PD-L1) tumor proportion score (TPS) ≥50%. Tumor mutation burden (TMB) also predicts response to ICIs but is often not available in real time for decision making in the first-line setting. Smoking exposure can be a proxy for TMB in NSCLC. The impact of smoking status on efficacy of PD-1 blockade in NSCLC patients with PD-L1 TPS ≥50% has not been well defined. PATIENTS AND METHODS: To investigate the relationship between smoking and activity of ICIs in NSCLC, we retrospectively studied 315 patients with NSCLC and PD-L1 TPS ≥50% at five USA academic medical centers. Objective response rates (ORRs), progression-free survival (PFS), and duration of response (DOR) were compared between never (<100 lifetime cigarettes), light (≤10 pack-years), and heavy (>10 pack-years) smokers. A subset of patients underwent next-generation sequencing to estimate TMB. RESULTS: We identified 36 (11%) never, 42 (13%) light, and 237 (75%) heavy smokers with NSCLC and PD-L1 TPS ≥50% treated with ICIs. Objective responses were observed in 27%, 40%, and 40% of never, light, and heavy smokers, respectively (P = 0.180 never versus heavy; P = 1.000 light versus heavy). Median PFS and median DOR were numerically shorter in never and light smokers compared with heavy smokers (PFS 3.0 versus 4.0 versus 5.4 months; median DOR 6.9 versus 10.8 versus 17.8 months), but were not statistically different [PFS: hazard ratio (HR) 1.37, P = 0.135 and HR 1.24, P = 0.272; DOR: HR 1.92, P = 0.217 and HR 1.79, P = 0.141]. CONCLUSIONS: PD-(L)1 inhibitors are associated with antitumor activity in NSCLC with PD-L1 TPS ≥50% regardless of smoking status. Nevertheless, there is a signal of potentially decreased durability among never and light smokers that should be further evaluated. Distinct immunobiologic features may affect initial response versus durability of antitumor immunity to programmed cell death 1 (PD-1) blockade.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Fosfolipasa D/metabolismo , Apoptosis , Antígeno B7-H1/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Receptor de Muerte Celular Programada 1 , Estudios Retrospectivos , FumadoresRESUMEN
OBJECTIVE: To define the relationship of synovial B cells to clinical phenotypes at different stages of disease evolution and drug exposure in rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens and demographic and clinical data were collected from 2 RA cohorts (n = 329), one of patients with untreated early RA (n = 165) and one of patients with established RA with an inadequate response to tumor necrosis factor inhibitors (TNFi-IR; n = 164). Synovial tissue was subjected to hematoxylin and eosin and immunohistochemical staining and semiquantitative assessment for the degree of synovitis (on a scale of 0-9) and of CD20+ B cell infiltrate (on a scale of 0-4). B cell scores were validated by digital image analysis and B cell lineage-specific transcript analysis (RNA-Seq) in the early RA (n = 91) and TNFi-IR (n = 127) cohorts. Semiquantitative CD20 scores were used to classify patients as B cell rich (≥2) or B cell poor (<2). RESULTS: Semiquantitative B cell scores correlated with digital image analysis quantitative measurements and B cell lineage-specific transcripts. B cell-rich synovitis was present in 35% of patients in the early RA cohort and 47.7% of patients in the TNFi-IR cohort (P = 0.025). B cell-rich patients showed higher levels of disease activity and seropositivity for rheumatoid factor and anti-citrullinated protein antibody in early RA but not in established RA, while significantly higher histologic synovitis scores in B cell-rich patients were demonstrated in both cohorts. CONCLUSION: We describe a robust semiquantitative histologic B cell score that closely replicates the quantification of B cells by digital or molecular analyses. Our findings indicate an ongoing B cell-rich synovitis, which does not seem to be captured by standard clinimetric assessment, in a larger proportion of patients with established RA than early RA.
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Artritis Reumatoide/complicaciones , Artritis Reumatoide/tratamiento farmacológico , Linfocitos B , Sinovitis/complicaciones , Sinovitis/genética , Adulto , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fenotipo , Sinovitis/inmunologíaRESUMEN
BACKGROUND: In non-small-cell lung cancers with programmed death-ligand 1 (PD-L1) expression on ≥50% of tumor cells, first-line treatment with the PD-1 inhibitor pembrolizumab improves survival compared with platinum-doublet chemotherapy. Whether higher PD-L1 levels within the expression range of 50%-100% predict for even greater benefit to pembrolizumab is currently unknown. PATIENTS AND METHODS: In this multicenter retrospective analysis, we analyzed the impact of PD-L1 expression levels on the overall response rate (ORR), median progression-free survival (mPFS), and median overall survival (mOS) in patients who received commercial pembrolizumab as first-line treatment of non-small-cell lung cancer (NSCLC) with a PD-L1 expression of ≥50% and negative for genomic alterations in the EGFR and ALK genes . RESULTS: Among 187 patients included in this analysis, the ORR was 44.4% [95% confidence interval (CI) 37.1% to 51.8%], the mPFS was 6.5 months (95% CI 4.5-8.5), and the mOS was not reached. The median PD-L1 expression level among patients who experienced a response to pembrolizumab was significantly higher than among patients with stable or progressive disease (90% versus 75%, P < 0.001). Compared with patients with PD-L1 expression of 50%-89% (N = 107), patients with an expression level of 90%-100% (N = 80) had a significantly higher ORR (60.0% versus 32.7%, P < 0.001), a significantly longer mPFS [14.5 versus 4.1 months, hazard ratio (HR) 0.50 (95% CI 0.33-0.74), P < 0.01], and a significantly longer mOS [not reached versus 15.9 months, HR 0.39 (95% CI 0.21-0.70), P = 0.002]. CONCLUSION: Among patients with NSCLC and PD-L1 expression of ≥50% treated with first-line pembrolizumab, clinical outcomes are significantly improved in NSCLCs with a PD-L1 expression of ≥90%. These findings have implications for treatment selection as well as for clinical trial interpretation and design.
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Adenocarcinoma del Pulmón/mortalidad , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Escamosas/mortalidad , Neoplasias Pulmonares/mortalidad , Adenocarcinoma del Pulmón/tratamiento farmacológico , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Adulto , Anciano , Anciano de 80 o más Años , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor/inmunología , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Selección de Paciente , Pronóstico , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: Although EGFR mutant tumors exhibit low response rates to immune checkpoint blockade overall, some EGFR mutant tumors do respond to these therapies; however, there is a lack of understanding of the characteristics of EGFR mutant lung tumors responsive to immune checkpoint blockade. PATIENTS AND METHODS: We retrospectively analyzed de-identified clinical and molecular data on 171 cases of EGFR mutant lung tumors treated with immune checkpoint inhibitors from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, University of California Los Angeles, and Dana Farber Cancer Institute. A separate cohort of 383 EGFR mutant lung cancer cases with sequencing data available from the Yale Cancer Center, Memorial Sloan Kettering Cancer Center, and The Cancer Genome Atlas was compiled to assess the relationship between tumor mutation burden and specific EGFR alterations. RESULTS: Compared with 212 EGFR wild-type lung cancers, outcomes with programmed cell death 1 or programmed death-ligand 1 (PD-(L)1) blockade were worse in patients with lung tumors harboring alterations in exon 19 of EGFR (EGFRΔ19) but similar for EGFRL858R lung tumors. EGFRT790M status and PD-L1 expression did not impact response or survival outcomes to immune checkpoint blockade. PD-L1 expression was similar across EGFR alleles. Lung tumors with EGFRΔ19 alterations harbored a lower tumor mutation burden compared with EGFRL858R lung tumors despite similar smoking history. CONCLUSIONS: EGFR mutant tumors have generally low response to immune checkpoint inhibitors, but outcomes vary by allele. Understanding the heterogeneity of EGFR mutant tumors may be informative for establishing the benefits and uses of PD-(L)1 therapies for patients with this disease.
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Antineoplásicos Inmunológicos/farmacología , Biomarcadores de Tumor/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Anciano , Alelos , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/antagonistas & inhibidores , Antígeno B7-H1/inmunología , Antígeno B7-H1/metabolismo , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/metabolismo , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Resistencia a Antineoplásicos/genética , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/genética , Receptores ErbB/metabolismo , Femenino , Heterogeneidad Genética , Humanos , Pulmón/inmunología , Pulmón/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/mortalidad , Masculino , Persona de Mediana Edad , Mutación , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Supervivencia sin Progresión , Estudios Retrospectivos , Fumar Tabaco/efectos adversos , Fumar Tabaco/epidemiologíaRESUMEN
BACKGROUND: Concurrent programmed death-ligand-1 (PD-(L)1) plus osimertinib is associated with severe immune related adverse events (irAE) in epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC). Now that PD-(L)1 inhibitors are routinely used as adjuvant and first-line treatments, sequential PD-(L)1 inhibition followed by osimertinib use may become more frequent and have unforeseen serious toxicity. METHODS: We identified patients with EGFR-mutant NSCLC who were treated with PD-(L)1 blockade and EGFR- tyrosine kinase inhibitors (TKIs), irrespective of drug or sequence of administration (total n = 126). Patient records were reviewed to identify severe (NCI-CTCAE v5.0 grades 3-4) toxicity. RESULTS: Fifteen percent [6 of 41, 95% confidence interval (CI) 7% to 29%] of all patients treated with sequential PD-(L)1 blockade followed later by osimertinib developed a severe irAE. Severe irAEs were most common among those who began osimertinib within 3 months of prior PD-(L)1 blockade (5 of 21, 24%, 95% CI 10% to 45%), as compared with >3-12 months (1 of 8, 13%, 95% CI 0% to 50%), >12 months (0 of 12, 0%, 95% CI 0% to 28%). By contrast, no severe irAEs were identified among patients treated with osimertinib followed by PD-(L)1 (0 of 29, 95% CI 0% to 14%) or PD-(L)1 followed by other EGFR-TKIs (afatinib or erlotinib, 0 of 27, 95% CI 0% to 15%). IrAEs occurred at a median onset of 20 days after osimertinib (range 14-167 days). All patients with irAEs required steroids and most required hospitalization. CONCLUSION: PD-(L)1 blockade followed by osimertinib is associated with severe irAE and is most frequent among patients who recently received PD-(L)1 blockade. No irAEs were observed when osimertinib preceded PD-(L)1 blockade or when PD-(L)1 was followed by other EGFR-TKIs. This association appears to be specific to osimertinib, as no severe irAEs occurred with administration of other EGFR-TKIs.
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Antineoplásicos Inmunológicos/efectos adversos , Antígeno B7-H1/antagonistas & inhibidores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/inmunología , Acrilamidas/administración & dosificación , Adulto , Anciano , Anciano de 80 o más Años , Compuestos de Anilina/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos Inmunológicos/uso terapéutico , Antígeno B7-H1/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Receptores ErbB/genética , Receptores ErbB/inmunología , Femenino , Humanos , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Nivolumab/administración & dosificación , Neumonía/inducido químicamente , Neumonía/inmunología , Inhibidores de Proteínas Quinasas/efectos adversos , Inhibidores de Proteínas Quinasas/uso terapéutico , Estudios Retrospectivos , Adulto JovenAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Brentuximab Vedotina/uso terapéutico , Infecciones por VIH/complicaciones , Enfermedad de Hodgkin/complicaciones , Linfoma Anaplásico de Células Grandes/tratamiento farmacológico , Neoplasias Cutáneas/tratamiento farmacológico , Diagnóstico Diferencial , Humanos , Linfoma Anaplásico de Células Grandes/complicaciones , Linfoma Anaplásico de Células Grandes/diagnóstico , Linfoma Anaplásico de Células Grandes/patología , Masculino , Persona de Mediana Edad , Piel/patología , Neoplasias Cutáneas/complicaciones , Neoplasias Cutáneas/diagnóstico , Neoplasias Cutáneas/patologíaRESUMEN
Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were ß-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB-related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI.
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Antibacterianos/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Células Renales/mortalidad , Disbiosis/mortalidad , Neoplasias Renales/mortalidad , Neoplasias Pulmonares/mortalidad , Anciano , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Puntos de Control del Ciclo Celular/efectos de los fármacos , Disbiosis/inducido químicamente , Disbiosis/patología , Femenino , Estudios de Seguimiento , Humanos , Inmunoterapia/efectos adversos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Masculino , Nivolumab/efectos adversos , Pronóstico , Tasa de SupervivenciaRESUMEN
Background: Programmed cell death protein-1 (PD-1) blockade therapies have demonstrated durable responses and prolonged survival in a variety of malignancies. Treatment is generally well tolerated although immune-related adverse events (irAEs) can occur. Autoimmune thyroid dysfunction is among the most common irAE, but an assessment of the clinical, mechanistic, and immunologic features has not been previously described. Patient and methods: Patients with advanced non-small-cell lung cancer (NSCLC) treated with pembrolizumab at Memorial Sloan Kettering Cancer Center (n = 51) as part of KEYNOTE-001 (NCT01295827) were included. Thyroid function test and anti-thyroid antibodies were assessed prospectively at each study visit, beginning before the first treatment. Frequency of development of thyroid dysfunction, association with anti-thyroid antibodies, clinical course, and relationship with progression-free survival and overall survival to treatment with pembrolizumab was evaluated. Results: Of 51 patients treated, 3 were hypothyroid and 48 were not at baseline. Ten of 48 [21%, 95% confidence interval (CI) 10% to 35%] patients developed thyroid dysfunction requiring thyroid replacement. Anti-thyroid antibodies were present in 8 of 10 patients who developed thyroid dysfunction, compared with 3 of 38 who did not (80% versus 8%, P < 0.0001). Thyroid dysfunction occurred early (median, 42 days) in the pembrolizumab course, and a majority (6 of 10 patients) experienced brief, transient hyperthyroidism preceding the onset of hypothyroidism; no persistent hyperthyroidism occurred. Both hyperthyroidism and hypothyroidism were largely asymptomatic. Overall survival with pembrolizumab was significantly longer in subjects who developed thyroid dysfunction (hazard ratio, 0.29; 95% CI 0.09-0.94; P = 0.04). Conclusions: Thyroid dysfunction during pembrolizumab treatment of NSCLC is common and is characterized by early-onset, frequently preceded by transient hyperthyroidism, closely associated with anti-thyroid antibodies, and may be associated with improved outcomes. The presence of antibody-mediated toxicity in T-cell-directed therapy suggests an under-recognized impact of PD-1 biology in modulating humoral immunity.
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Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Hipertiroidismo/patología , Receptor de Muerte Celular Programada 1/genética , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/efectos adversos , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Hipertiroidismo/inducido químicamente , Hipertiroidismo/genética , Hipertiroidismo/inmunología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/patología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/inmunología , Glándula Tiroides/patologíaRESUMEN
AIMS: To study the expression of CD2-associated protein (CD2AP), an adaptor protein involved in T-cell signalling and renal function, in normal, reactive and neoplastic human lymphoid tissues. METHODS AND RESULTS: We used immunohistochemical techniques to evaluate monoclonal antibodies against CD2AP on over 400 formalin fixed paraffin embedded tissue blocks retrieved from the host institutions of three authors. The samples tested included normal, reactive and neoplastic lymphoid tissue. In lymphoid tissues, strong CD2AP staining was observed in plasmacytoid dendritic cells (pDCs), weak and variable in mantle zone B cells and moderate in rare germinal center cells. CD2AP labeled cortical and rare medullary thymocytes and isolated mononuclear cells in bone marrow trephines. Furthermore, epithelial and endothelial cells expressed CD2AP. Among neoplasms, the greatest number of CD2AP-positive cases were found in diffuse large B cell (21/94), NK T-cell lymphomas (7/67), "blastic plasmacytoid dendritic cell neoplasms" (9/10) and some types of solid tumor. CONCLUSIONS: Our finding that mature peripheral T cells are CD2AP-negative but immature cortical thymocytes are positive may prove useful for diagnostic purposes. Moreover, our results demonstrate that CD2AP represents a useful marker of normal and neoplastic pDC and may be used in a diagnostic panel in reactive or neoplastic lymphoid proliferations.
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Proteínas Adaptadoras Transductoras de Señales/metabolismo , Linfocitos B/metabolismo , Proteínas del Citoesqueleto/metabolismo , Células Dendríticas/metabolismo , Linfoma/diagnóstico , Linfoma/metabolismo , Timocitos/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Biomarcadores/metabolismo , Línea Celular , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/inmunología , Humanos , Inmunohistoquímica , Linfocitos/citologíaRESUMEN
The tuberculids are a group of rare cutaneous hypersensitivity reactions that occur in response to a distant focus of mycobacterial infection. Typically, Mantoux testing is strongly reactive, and clinical response to antituberculous treatment is rapid. The papulonecrotic subtype is one such clinical variant, consisting of multiple symmetrical papules, often with central necrosis, distributed preferentially over the trunk and limbs. Localized forms are rare, and mainly involve the genitalia in men. We describe a 26-year-old Indian woman with lymphatic and pulmonary tuberculosis (TB) in association with localized papulonecrotic tuberculid of the vulva, which resolved promptly on treating the underlying TB.
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Tuberculosis Cutánea/diagnóstico , Tuberculosis de los Genitales Femeninos/diagnóstico , Enfermedades de la Vulva/diagnóstico , Adulto , Biopsia , Femenino , Humanos , Necrosis , Perineo/patología , Tuberculosis Cutánea/patología , Tuberculosis de los Genitales Femeninos/patología , Vulva/patología , Enfermedades de la Vulva/patologíaRESUMEN
A newly isolated strain of Leuconostoc mesenteroides (PCSIR-3) produced a different dextran compared with that of L. mesenteroides NRRL B-512F. Different media compositions used for dextran production showed that media containing CaCl(2) produced dextran in higher quantities compared with other media. The viscosity of the dextran produced in different media varied in nature. Dextran from media 1 and 2 was of higher molecular mass compared with that from media 3, 4 and 5. Dextran production is also effected by the sucrose concentration in the media. The higher the initial concentration of sucrose, the higher is the yield of dextran produced per unit volume; however, the percentage conversion of sucrose into dextran decreases. A continuous drop in pH was associated with growth and dextran production. The yield of dextran increases during the growth phase and maximum yield was obtained at the end of the exponential phase. Dextran produced by L. mesenteroides PCSIR-3 is quite different from the dextran produced by NRRL B-512F. Maximum dextran production from L. mesenteroides PCSIR-3 occurs in 18 h compared with 12 h for NRRL B-512F.
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Dextranos/biosíntesis , Leuconostoc/aislamiento & purificación , Leuconostoc/metabolismo , Sacarosa/metabolismo , Proteínas Bacterianas/metabolismo , Dextranos/metabolismo , Fermentación , Concentración de Iones de Hidrógeno , Leuconostoc/enzimología , Leuconostoc/crecimiento & desarrollo , Estándares de Referencia , Especificidad de la Especie , Sacarasa/metabolismo , Factores de TiempoRESUMEN
Mycophenolic acid sodium salt (ERL080) is currently in Phase III clinical trials for the prophylaxis of kidney transplant rejection upon coadministration with Neoral (cyclosporin A microemulsion). To assess the relative side effect profile of ERL080 and MMF as drug substances in Lewis rats, a rat strain commonly used in transplantation experiments, a comparative 4-week tolerability study was performed. Escalating doses of ERL080 and MMF were administered orally at 10-30 mg/kg/d (i.e., doses within or above the immunosuppressive range in rats), either in single compound treatment or in combination with cyclosporine (CsA) at a daily oral dose of 7.5 mg/kg. The compounds were well tolerated as documented by body weight monitoring, hematologic parameters, and weight and histology of organs. Major abnormalities observed were a dose-dependent reduction in thymus weight associated with immunosuppression, in some cases villous atrophy in the jejunum, a reduction in white blood cell counts and lymphocyte counts (mean value in distinct treatment groups not exceeding 40-50%), a decrease in red blood cell counts and hemoglobin concentration (at maximum 25-30%), and an increase in platelet counts (in some groups up to doubling). At a given dose, these adverse effects were slightly more pronounced for MMF than for ERL080, and for groups under CsA coadministration compared to both compounds given alone. No significant potentiation effect of CsA on the changes induced by ERL080 or MMF was observed. Moreover, there were no new toxic entities evident upon CsA microemulsion coadministration.
Asunto(s)
Ciclosporina/toxicidad , Inmunosupresores/toxicidad , Ácido Micofenólico/análogos & derivados , Ácido Micofenólico/toxicidad , Animales , Recuento de Células Sanguíneas , Relación Dosis-Respuesta a Droga , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Endogámicas LewRESUMEN
BACKGROUND: A variety of factors can adversely impact chronic peritoneal dialysis (CPD) as an effective renal replacement therapy for patients with end-stage renal disease. These factors include peritonitis, poor clearances, loss of ultrafiltration, and a variety of anatomic problems, such as hernias, peritoneal fluid leaks, loculations, and catheter-related problems caused by omental blockage. This study reviews our experience with peritoneal scintigraphy for the evaluation of some of these difficulties. METHODS: From 1991 to 1996, 50 peritoneal scintigraphy scans were obtained in 48 CPD patients. Indications for scintigraphy were evaluated, and the patients were placed into four groups: group I, abdominal wall swelling; group II, inguinal or genital swelling; group III, pleural fluid; and group IV, poor drainage and/or poor ultrafiltration. A peritoneal scintigraphy protocol was established and the radiotracer isotope that was used was 2.0 mCi of 99mtechnetium sulfur colloid placed in two liters of 2.5% dextrose peritoneal dialysis solution. RESULTS: Ten scans were obtained to study abdominal wall swelling, with seven scans demonstrating leaks; six of these episodes improved with low-volume exchanges. Twenty scans were obtained to evaluate inguinal or genital swelling, and 10 of these had scintigraphic evidence for an inguinal hernia leak (9 of these were surgically corrected). One of four scans obtained to evaluate a pleural fluid collection demonstrated a peritoneal-pleural leak that corrected with a temporary discontinuation of CPD. Sixteen scans were obtained to assess poor drainage and/or ultrafiltration. Five of these scans demonstrated peritoneal location, and all of these patients required transfer to hemodialysis. The other 11 scans were normal; four patients underwent omentectomies, allowing three patients to continue with CPD. CONCLUSION: Peritoneal scintigraphy is useful in the evaluation and assessment of CPD patients who develop anatomical problems (such as anterior abdominal, pleural-peritoneal, inguinal, and genital leaks) and problems with ultrafiltration and/or drainage.