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1.
Oncologist ; 28(6): e379-e390, 2023 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-36821637

RESUMO

BACKGROUND: Clinical trials of immune checkpoint inhibitors (ICIs) often do not include patients with advanced chronic kidney disease (CKD). We aimed to determine the safety of ICIs in patients with cancer and advanced CKD (stages 4-5 CKD, estimated glomerular filtration rate [eGFR] <30 mL/minute/1.73 m2). PATIENTS AND METHODS: Patients with advanced CKD from the Mass General Brigham network who received ICIs (n = 91) were compared against those receiving nephrotoxic (n = 113) and non-nephrotoxic (n = 130) antineoplastic therapies, respectively. Rates of new-onset kidney failure (end-stage kidney disease or sustained eGFR ≤10 mL/minute/1.73 m2) and AKI were compared. Among ICI-treated patients, we modeled Fine-Gray subdistribution hazards to compare immune-related adverse event (irAE) risk and used Kaplan-Meier analysis to compare overall survival in patients with advanced CKD to those with eGFR ≥30 mL/minute/1.73 m2. RESULTS: Rates of new-onset kidney failure were similar at 1 year following initiation of ICIs (10.0%), nephrotoxic (6.2%), and non-nephrotoxic antineoplastic therapies (9.3%) (P = .28). AKI rates were also similar: 17.5%, 17.6%, and 20% of patients in each cohort, respectively (P = .87). Advanced CKD did not increase the risk of developing irAEs (adjusted hazard ratio [HR] 1.28, 95% CI, 0.91-1.81). However, patients with advanced CKD who received ICIs had a decreased overall survival compared with patients with eGFR ≥30 mL/minute/1.73 m2 (HR 1.30 for death, 95% CI, 1.02-1.66, P = .03). CONCLUSION: ICIs are not associated with increased risk of AKI or new-onset kidney failure compared with other antineoplastic therapies in patients with advanced CKD. Advanced CKD did not increase the risk of extra-renal irAEs, although these patients suffered from lower overall survival.


Assuntos
Injúria Renal Aguda , Antineoplásicos , Insuficiência Renal Crônica , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Insuficiência Renal Crônica/complicações
3.
J Immunother Cancer ; 10(6)2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35705313

RESUMO

BACKGROUND: Immune checkpoint inhibitors (ICIs) have improved survival and are increasingly used for non-small cell lung cancer. However, use may be limited by immune-related adverse events such as checkpoint-inhibitor pneumonitis (CIP). Literature estimates for CIP incidence are inconsistent. Real-world adherence to guidelines, clinical course, and healthcare utilization in the treatment of CIP has not been described in large cohorts. METHODS: A combined claims and electronic health record database (TriNetX) was used to identify 13,113 patients with lung cancer treated with programmed cell death receptor/ligand 1 (PD-1/PD-L1) inhibitors, and a propensity score-matched control cohort treated with chemotherapy or targeted therapies. The attributable risk of CIP was calculated in the first 12 months after therapy by comparing the incidence of diagnosis codes for pneumonitis/pneumonia between cohorts. Cases of CIP, identified by the most specific code for drug-induced respiratory conditions, were further analyzed for medication usage, rates of diagnostic bronchoscopy, ICI discontinuation rates, and usage of hospital services compared with patients receiving PD-1/PD-L1 inhibitors who did not develop CIP. RESULTS: The attributable risk of pneumonitis to PD-1/PD-L1 inhibitors was 2.49% (95% CI, 1.50% to 3.47%). Median time to onset in the CIP subcohort was 3.9 months (IQR, 2.1-7.3 months). Steroid and antibiotic use increased dramatically after a pneumonitis diagnosis, and 70.2% of patients permanently discontinued ICI therapy. Compared with controls, patients with CIP had more than a threefold increased risk of needing critical care (relative risk 3.59, 95% CI, 2.31 to 5.57) and an increased risk of mortality (HR 2.34, 95% CI, 1.47 to 3.71). CONCLUSIONS: In a large claims-based analysis, PD-1/PD-L1 inhibitors increase the risk of pneumonitis in patients with lung cancer by 2.49%. Cases of CIP are associated with high healthcare utilization, discontinuation of ICIs, and mortality.


Assuntos
Antineoplásicos Imunológicos , Carcinoma Pulmonar de Células não Pequenas , Inibidores de Checkpoint Imunológico , Neoplasias Pulmonares , Pneumonia , Antineoplásicos Imunológicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos de Coortes , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Incidência , Neoplasias Pulmonares/tratamento farmacológico , Pneumonia/induzido quimicamente , Pneumonia/diagnóstico , Pneumonia/epidemiologia , Receptor de Morte Celular Programada 1
4.
J Natl Cancer Inst ; 114(8): 1200-1202, 2022 08 08.
Artigo em Inglês | MEDLINE | ID: mdl-35188215

RESUMO

Although indications for immune checkpoint inhibitors (ICIs) have dramatically increased in the past decade, ICIs have been associated with autoinflammatory immune-related adverse events, which can resemble autoimmune diseases (ADs). Little is known about the impact of baseline AD on mortality in cancer patients treated with ICIs. Here, we identified 17 497 patients with preexisting autoimmune diagnoses prior to treatment with antiprogrammed cell death receptor-1 or antiprogrammed cell death ligand-1 therapy and 17 497 matched controls through the TriNetX Diamond network of more than 200 million patients across the United States and Europe. Using a Cox proportional hazards model, we found that patients with history of AD were not at higher risk of mortality than non-AD patients (hazard ratio [HR] = 1.03, 95% confidence interval [CI] = 1 to 1.07; P = .05). Additionally, history of Hashimoto disease (HR = 0.75, 95% CI = 0.62 to 0.90; P = .002) and vitiligo (HR = 0.52, 95% CI = 0.34 to 0.81; P = .003) were statistically significantly associated with decreased mortality. This suggests that underlying AD need not be a contraindication to inclusion in clinical trials and administration of ICI for treatment of cancer.


Assuntos
Antineoplásicos Imunológicos , Doenças Autoimunes , Neoplasias , Antineoplásicos Imunológicos/efeitos adversos , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/complicações , Doenças Autoimunes/tratamento farmacológico , Antígeno B7-H1 , Humanos , Neoplasias/complicações , Receptor de Morte Celular Programada 1 , Estados Unidos
5.
JAMA Dermatol ; 158(2): 189-193, 2022 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-35019948

RESUMO

IMPORTANCE: Despite the efficacy of immune checkpoint inhibitors (ICIs), cutaneous immune-related adverse events (cirAEs) occur in 20% to 40% of all treated patients. To our knowledge, little is known about the predictive value of these cutaneous eruptions and their subtypes regarding cancer survival. OBJECTIVE: To determine the association of developing cirAEs following treatment with anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) therapy with patient survival. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study used data from the TriNetX Diamond Network, a database of health records and claims data from more than 200 million US and European patients, to conduct a population-level cohort analysis. The study included 7008 eligible patients who developed cirAEs after treatment with anti-PD-1 or anti-PD-L1 therapy for malignant neoplasms of digestive organs, bronchus or lung, melanoma of skin, and urinary tract who were identified through the TriNetX Diamond Network along with 7008 matched controls. EXPOSURES: Development of cirAEs within 6 months following anti-PD-1 or anti-PD-L1 therapy. MAIN OUTCOMES AND MEASURES: A 6-month analysis using a Cox proportional hazards model was performed to determine the association of cirAEs with overall survival after adjusting for demographic characteristics, cancer type, and cancer stage. RESULTS: A total of 7008 patients (3036 women [43.3%]; mean [SD] age, 68.2 [11.2] years) were matched to 7008 (3044 women [43.4%]; mean [SD] age, 68.3 [11.1] years) controls. Pruritus (hazard ratio [HR], 0.695; 95% CI, 0.602-0.803; P < .001), drug eruption (HR, 0.755; 95% CI, 0.635-0.897; P = .001), xerosis (HR, 0.626; 95% CI, 0.469-0.834; P = .001), nonspecific rashes (HR, 0.704; 95% CI, 0.634-0.781; P < .001), and appearance of any cirAE (HR, 0.778; 95% CI, 0.726-0.834; P < .001) were significantly protective of mortality using a Benjamini-Hochberg correction with a significance level of .05. Additionally, psoriasis (HR, 0.703; 95% CI, 0.497-0.994; P = .045) and lichen planus/lichenoid dermatitis (HR, 0.511; 95% CI, 0.279-0.939; P = .03) were significant. Eczematous dermatitis (HR, 0.612; 95% CI, 0.314-1.195), vitiligo (HR, 0.534; 95% CI, 0.254-1.123), bullous pemphigoid (HR, 0.524; 95% CI, 0.140-1.956), and Grover disease (HR, 0.468; 95% CI, 0.115-1.898) were all associated with strong protective clinical effects. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that the development of cirAEs is strongly associated with response to ICI therapy and patient survival.


Assuntos
Neoplasias Pulmonares , Melanoma , Idoso , Antígeno B7-H1/metabolismo , Estudos de Coortes , Feminino , Humanos , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Melanoma/tratamento farmacológico , Estudos Retrospectivos , Pele/patologia
6.
Postgrad Med ; 133(sup1): 71-79, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34255597

RESUMO

Cancer is a leading cause of venous thromboembolism (VTE), which contributes to significant morbidity and mortality in these patients. Increased thrombotic risk in cancer patients is modified by tumor-specific biology, disease-directed interventions, and individual comorbidities. Risk stratification for prophylaxis and treatment requires regular reevaluation of these factors, which can be facilitated by validated prediction tools. This review also discusses large clinical trial data (SELECT-D, HOKUSAI-VTE, ADAM VTE, CARAVAGGIO) demonstrating that direct oral anticoagulants (DOACs) are effective in the treatment of cancer-associated VTE, with comparable efficacy to the traditional choice of low molecular weight heparin. In the prophylactic setting derived from patients with cancer with increased VTE risk, DOACs also reduced the incidence of VTE with only modest increases in bleeding risk. The ease of DOAC administration and acceptable risk profile in the carefully selected patient make them an appealing choice for anticoagulation. In instances where the risk of gastrointestinal bleeding is of concern, apixaban, in particular, may still be a suitable option in place of LMWH. These improvements in our anticoagulation approach to cancer-associated VTE are well-timed to accompany the recent advances in disease-directed therapies that are enabling patients to live longer with cancer and therefore at increased risk of complications such as VTE.


Assuntos
Anticoagulantes/farmacologia , Quimioprevenção , Neoplasias/complicações , Risco Ajustado/métodos , Medição de Risco/métodos , Tromboembolia Venosa , Quimioprevenção/métodos , Quimioprevenção/tendências , Humanos , Seleção de Pacientes , Resultado do Tratamento , Tromboembolia Venosa/etiologia , Tromboembolia Venosa/prevenção & controle
7.
Oncotarget ; 7(8): 8653-62, 2016 Feb 23.
Artigo em Inglês | MEDLINE | ID: mdl-26840025

RESUMO

The transcription factor CREB (cAMP Response Element Binding Protein) is an important determinant in the growth of Acute Myeloid Leukemia (AML) cells. CREB overexpression increases AML cell growth by driving the expression of key regulators of apoptosis and the cell cycle. Conversely, CREB knockdown inhibits proliferation and survival of AML cells but not normal hematopoietic cells. Thus, CREB represents a promising drug target for the treatment of AML, which carries a poor prognosis. In this study, we performed a high-throughput small molecule screen to identify compounds that disrupt CREB function in AML cells. We screened ~114,000 candidate compounds from Stanford University's small molecule library, and identified 5 molecules that inhibit CREB function at micromolar concentrations, but are non-toxic to normal hematopoietic cells. This study suggests that targeting CREB function using small molecules could provide alternative approaches to treat AML.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/antagonistas & inibidores , Ensaios de Triagem em Larga Escala/métodos , Leucemia Mieloide Aguda/tratamento farmacológico , Leucemia Mieloide Aguda/patologia , Regiões Promotoras Genéticas/genética , Elementos de Resposta/genética , Bibliotecas de Moléculas Pequenas/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/efeitos dos fármacos , Células-Tronco Hematopoéticas/metabolismo , Humanos , Leucemia Mieloide Aguda/metabolismo , Luciferases/metabolismo , RNA Mensageiro/genética , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
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