RESUMO
AIM: While both efficacy and safety of anti-PD-1 agents seem to be independent of previous treatment with anti-CTLA-4, limited data exist of efficacy and toxicity of ipilimumab after progression on anti-PD-1 therapy. This retrospective analysis describes the efficacy and safety of sequential therapy with ipilimumab in patients with metastatic melanoma who progressed on anti-PD-1 antibody. METHODS: Nine patients who progressed on anti-PD-1 therapy received four cycles of ipilimumab 3 mg/kg every 3 weeks. RESULTS: Two out of nine patients (2/9; 22.2%) showed a partial response, and seven patients (7/9; 77.8%) experienced disease progression. Median progression-free survival was 3.14 months (95% CI: 2.56-3.71), and the median overall survival since the start of anti-PD-1 therapy was 16.8 months (95% CI: 8.1-25.4). Five (5/9; 55.6%) patients experienced grade 3 immune-related adverse events. No grade 4 or 5 adverse events were reported. CONCLUSION: In this small retrospective series of cases, the efficacy of ipilimumab post-anti-PD-1 was similar to that described in the previous reports on ipilimumab.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Antígeno CTLA-4/antagonistas & inibidores , Melanoma/tratamento farmacológico , Melanoma/patologia , Terapia de Alvo Molecular , Idoso , Anticorpos Monoclonais/farmacologia , Antineoplásicos/farmacologia , Progressão da Doença , Feminino , Humanos , Ipilimumab , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Retratamento , Resultado do TratamentoRESUMO
Alternative splicing contributes to shaping lineage-specific gene expression and phenotypes. In this issue of Cell Genomics, Recinos, Bao, Wang, et al.1 report that the balance between splicing isoforms of the microtubule-associated protein Tau in the brain is differentially regulated among primates by the RNA-binding protein MBNL2, with consequences for protein aggregation and neurodegeneration in humans.
Assuntos
Processamento Alternativo , Encéfalo , Humanos , Processamento Alternativo/genética , Encéfalo/metabolismo , Encéfalo/crescimento & desenvolvimento , Animais , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Proteínas tau/metabolismo , Proteínas tau/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismoRESUMO
Resistance to MAPK inhibitors (MAPKi), the main cause of relapse in BRAF-mutant melanoma, is associated with the production of alternative BRAF mRNA isoforms (altBRAFs) in up to 30% of patients receiving BRAF inhibitor monotherapy. These altBRAFs have been described as being generated by alternative pre-mRNA splicing, and splicing modulation has been proposed as a therapeutic strategy to overcome resistance. In contrast, we report that altBRAFs are generated through genomic deletions. Using different in vitro models of altBRAF-mediated melanoma resistance, we demonstrate the production of altBRAFs exclusively from the BRAF V600E allele, correlating with corresponding genomic deletions. Genomic deletions are also detected in tumor samples from melanoma and breast cancer patients expressing altBRAFs. Along with the identification of altBRAFs in BRAF wild-type and in MAPKi-naive melanoma samples, our results represent a major shift in our understanding of mechanisms leading to the generation of BRAF transcripts variants associated with resistance in melanoma.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Melanoma , Inibidores de Proteínas Quinases , Proteínas Proto-Oncogênicas B-raf , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Melanoma/genética , Melanoma/tratamento farmacológico , Melanoma/patologia , Humanos , Resistencia a Medicamentos Antineoplásicos/genética , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral , Isoformas de Proteínas/metabolismo , Isoformas de Proteínas/genética , Processamento Alternativo/genética , Feminino , Deleção de GenesRESUMO
BACKGROUND: Melanoma is the cancer with the highest risk of dissemination to the central nervous system (CNS), one of the leading causes of mortality from this cancer. OBJECTIVE: To identify patients at higher risk of developing CNS metastases and to evaluate associated prognostic factors. METHODS: A cohort study (1998-2023) assessed patients who developed CNS melanoma metastases. Multivariate logistic regression was used to identify predictive factors at melanoma diagnosis for CNS metastasis. Cox regression analysis evaluated the CNS-independent metastasis-related variables impacting survival. RESULTS: Out of 4718 patients, 380 (8.05%) developed CNS metastases. Multivariate logistic regression showed that a higher Breslow index, mitotic rate ≥ 1 mm2, ulceration, and microscopic satellitosis were significant risk factors for CNS metastasis development. Higher patient age and the location of the primary tumor in the upper or lower extremities were protective factors. In survival analysis, post-CNS metastasis, symptomatic disease, prior non-CNS metastases, CNS debut with multiple metastases, elevated LDH levels, and leptomeningeal involvement correlated with poorer survival. CONCLUSION: Predictive factors in the primary tumor independently associated with brain metastases include microscopic satellitosis, ulceration, higher Breslow index, and trunk location. Prognostic factors for lower survival in CNS disease include symptomatic disease, multiple CNS metastases, and previous metastases from different sites.
RESUMO
BACKGROUND: The combination of anti-PD-1 and anti-CTLA-4 has been associated with improvement in response and survival over anti-PD-1 monotherapy in unselected patients with advanced melanoma. Whether patients with liver metastases also benefit from the combination of anti-PD-1 and anti-CTLA-4 over anti-PD-1, is unclear. In this study, we sought to assess whether the combination of anti-PD-1 and anti-CTLA-4 leads to better response, progression-free survival and overall survival, compared with anti-PD-1 monotherapy for patients with liver metastases. METHODS: We have conducted an international multicentre retrospective study. Patients with advanced melanoma with liver metastases treated with 1st line anti-PD1 monotherapy or with anti-CTLA-4 were included. The endpoints of this study were: objective response rate, progression-free survival and overall survival. RESULTS: With a median follow-up from commencement of anti-PD-1 monotherapy or in combination with anti-CTLA-4 of 47 months (95% CI, 42-51), objective response rate was higher with combination therapy (47%) versus anti-PD-1 monotherapy (35%) (p = 0.0027), while progression-free survival and overall survival were not statistically different between both treatment groups. However, on multivariable analysis with multiple imputation for missing values and adjusting for predefined variables, combination of anti-PD1 and anti-CTLA-4 was associated with higher objective response (OR 2.21, 1.46 - 3.36; p < 0.001), progression-free survival (HR 0.73, 0.57 - 0.92; p = 0.009) and overall survival (HR 0.71, 0.54 - 0.94; p = 0.018) compared to anti-PD1 monotherapy. CONCLUSIONS: Findings from this study will help guide treatment selection for patients who present with liver metastases, suggesting that combination therapy should be considered for this group of patients.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Antígeno CTLA-4 , Inibidores de Checkpoint Imunológico , Neoplasias Hepáticas , Melanoma , Receptor de Morte Celular Programada 1 , Humanos , Melanoma/tratamento farmacológico , Melanoma/secundário , Melanoma/mortalidade , Masculino , Estudos Retrospectivos , Feminino , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Pessoa de Meia-Idade , Antígeno CTLA-4/antagonistas & inibidores , Idoso , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Inibidores de Checkpoint Imunológico/uso terapêutico , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Idoso de 80 Anos ou mais , Intervalo Livre de Progressão , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/mortalidadeRESUMO
Immune-related adverse events (irAEs) are frequent and could be associated with improved response to immune checkpoint inhibitors (ICIs). A prospective cohort of advanced melanoma patients receiving ICI as first-line therapy was retrospectively reviewed (January 2011−February 2019). A total of 116 of 153 patients presented with at least one irAE (75.8%). The most frequent irAEs were dermatological (derm irAEs, 50%), asthenia (38%), and gastrointestinal (29%). Most irAEs appeared within the first 90 days, while 11.2% appeared after discontinuation of the therapy. Mild grade 1−2 derm irAEs tended to appear within the first 2 months of therapy with a median time of 65.5 days (IQR 26-139.25), while grade 3−4 derm irAEs appeared later (median 114 days; IQR 69-218) and could be detected at any time during therapy. Only derm irAE occurrence was related to improved survival (HR 6.46). Patients presenting derm irAEs showed better 5-year overall survival compared to those with no derm irAEs (53.1% versus 24.9%; p < 0.001). However, the difference was not significant when adjusting for the duration of therapy. In conclusion: the timeline of immune-related-AEs differs according to the organ involved. The (apparent) improved survival of patients who present derm AEs during immunotherapy could be partially explained by longer times under treatment.
RESUMO
Aim: To evaluate the safety of rechallenge with a different anti-PD-1 antibody after an immune-related adverse event (irAE) that has prompted the discontinuation of anti-PD-1 therapy. Patients & methods: We describe two patients with metastatic melanoma who developed potentially disabling and early irAEs following anti-PD-1 treatment. Therapy was discontinued and toxicities resolved with corticosteroids. Results: Rechallenge switching to an alternative anti-PD-1 antibody did not lead to a new or recurrent irAE. Conclusion: Switching to a different anti-PD-1 antibody when resuming therapy after an irAE might be a safe strategy and warrants further investigation. Structural and biological differences between antibodies might explain the different safety outcomes.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Substituição de Medicamentos , Inibidores de Checkpoint Imunológico/uso terapêutico , Nefrite/induzido quimicamente , Nivolumabe/uso terapêutico , Idoso , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológicoRESUMO
BACKGROUND: The role of perfusion computed tomography (pCT) in detecting changes in tumor vascularization as part of a response to antiangiogenic therapy in non-small cell lung cancer (NSCLC) remains unclear. METHODS: In this prospective pilot study (IMPACT trial, NCT02316327), we aimed to determine the ability of pCT to detect early changes in blood flow (BF), blood volume (BV), and permeability (PMB), and to explore whether these changes could predict the response at day +42 in patients with advanced, treatment-naive, non-squamous NSCLC treated with cisplatin and gemcitabine plus bevacizumab. RESULTS: All of the perfusion parameters showed a consistent decrease during the course of treatment. The BV difference between baseline and early assessment was significant (p = 0.013), whereas all perfusion parameters showed significant differences between baseline and day +42 (p = 0.003, p = 0.049, and p = 0.002, respectively). Among the 16 patients evaluable for efficacy, a significant decline in BV at day +7 from baseline was observed in tumors with no response (p = 0.0418). CONCLUSIONS: Our results confirm that pCT can capture early changes in tumor vasculature. A substantial early decline of BV from baseline might identify tumors less likely responsive to antiangiogenic-drugs.
RESUMO
Diabetes is a rare, but potentially life-threatening, adverse event of immune checkpoint inhibitors that requires prompt recognition and treatment. It usually occurs in the first 3 months of treatment and is typically related to programmed cell death-1 antibodies, alone or in combined therapy. It has rarely been described developing after immunotherapy cessation. We present a 51-year-old man with metastatic melanoma, who developed acute-onset diabetes 52 days after combined immunotherapy cessation with nivolumab and ipilimumab, and 25.6 months after receiving the first dose. He presented with acute hyperglycemic symptoms, ketosis, complete insulin depletion and negative autoimmunity, fulfilling the criteria of fulminant type 1 diabetes. The patient had previously developed hypophysitis with isolated adrenocorticotropic hormone deficiency during immunotherapy. We describe a case of late-onset fulminant type 1 diabetes developing after immunotherapy cessation. Patient education and active follow up after immunotherapy discontinuation are crucial to warrant a timely intervention.
Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Diabetes Mellitus Tipo 1/induzido quimicamente , Hipofisite/induzido quimicamente , Imunoterapia/efeitos adversos , Suspensão de Tratamento , Humanos , Ipilimumab/efeitos adversos , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Nivolumabe/efeitos adversosRESUMO
OBJECTIVES: To develop a risk model to predict 30-day mortality after emergency department treatment for COVID-19. MATERIAL AND METHODS: Observational retrospective cohort study including 2511 patients with COVID-19 who came to our emergency department between March 1 and April 30, 2020. We analyzed variables with Kaplan Meier survival and Cox regression analyses. RESULTS: All-cause mortality was 8% at 30 days. Independent variables associated with higher risk of mortality were age over 50 years, a Barthel index score less than 90, altered mental status, the ratio of arterial oxygen saturation to the fraction of inspired oxygen (SaO2/FIO2), abnormal lung sounds, platelet concentration less than 100 000/mm3, a C-reactive protein concentration of 5 mg/dL or higher, and a glomerular filtration rate less than 45 mL/min. Each independent predictor was assigned 1 point in the score except age, which was assigned 2 points. Risk was distributed in 3 levels: low risk (score of 4 points or less), intermediate risk (5 to 6 points), and high risk (7 points or above). Thirty-day risk of mortality was 1.7% for patients who scored in the low-risk category, 28.2% for patients with an intermediate risk score, and 67.3% for those with a high risk score. CONCLUSION: This mortality risk stratification tool for patients with COVID-19 could be useful for managing the course of disease and assigning health care resources in the emergency department.
OBJETIVO: Derivar un modelo de riesgo para estimar la probabilidad de mortalidad a los 30 días de la visita a urgencias de pacientes con COVID-19. METODO: Estudio observacional de cohortes retrospectivo de 2.511 pacientes con COVID-19 atendidos en el servicio de urgencias hospitalario (SUH) del 1 de marzo al 30 de abril de 2020. Se realizó análisis de supervivencia mediante Kaplan Meier y regresión de Cox. RESULTADOS: La mortalidad por cualquier causa a los 30 días fue de un 8%. Los factores asociados de forma independiente a mayor mortalidad fueron: edad 50 años, índice de Barthel 90 puntos, alteración del nivel de consciencia, índice de SaO2/FIO2 400, auscultación respiratoria anómala, cifra de plaquetas 100.000/mm3, PCR 5 mg/dL y filtrado glomerular 45 mL/min. A estos factores se les asignó una puntuación de 1, excepto a la edad, que se le asignó un valor de 2 puntos. Se dividió el modelo de riesgo en 3 categorías: riesgo bajo (menor o igual a 4 puntos), riesgo intermedio (5-6 puntos) y riesgo alto (igual o superior a 7 puntos). Para los pacientes clasificados como de bajo riesgo la probabilidad de mortalidad a los 30 días fue del 1,7%, en los casos de riesgo intermedio fue del 28,2% y para los de alto riesgo fue del 67,3%. CONCLUSIONES: Disponer de una herramienta para estratificar el riesgo de mortalidad de los pacientes con COVID-19 que consultan a un SUH podría ser de utilidad para la gestión de los recursos sanitarios disponibles.
Assuntos
COVID-19/mortalidade , Serviço Hospitalar de Emergência/estatística & dados numéricos , Modelos Teóricos , Proteína C-Reativa , Taxa de Filtração Glomerular , Humanos , Estimativa de Kaplan-Meier , Pulmão/fisiopatologia , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Centros de Atenção TerciáriaRESUMO
OBJECTIVES: To analyze emergency department (ED) revisits from patients discharged with possible coronavirus disease 2019 (COVID-19). MATERIAL AND METHODS: Retrospective observational study of consecutive patients who came to the ED over a period of 2 months and were diagnosed with possible COVID-19. We analyzed clinical and epidemiologic variables, treatments given in the ED, discharge destination, need to revisit, and reasons for revisits. Patients who did or did not revisit were compared, and factors associated with revisits were explored. RESULTS: The 2378 patients included had a mean age of 57 years; 49% were women. Of the 925 patients (39%) discharged, 170 (20.5%) revisited the ED, mainly for persistence or progression of symptoms. Sixty-six (38.8%) were hospitalized. Odds ratios (ORs) for the following factors showed an association with revisits: history of rheumatologic disease (OR, 2.97; 95% CI, 1.10-7.99; P = .03), digestive symptoms (OR, 1.73; 95% CI, 1.14-2.63; P = .01), respiratory rate over 20 breaths per minute (OR, 1.03; 95% CI, 1.0-1.06; P = .05), and corticosteroid therapy given in the ED (OR, 7.78; 95% CI, 1.77-14.21, P = .01). Factors associated with hospitalization after revisits were age over 48 years (OR, 2.57; 95% CI, 1 42-4.67; P = .002) and fever (OR, 4.73; 95% CI, 1.99-11.27; P = .001). CONCLUSION: Patients under the age of 48 years without comorbidity and with normal vitals can be discharged from the ED without fear of complications. A history of rheumatologic disease, fever, digestive symptoms, and a respiratory rate over 20 breaths per minute, or a need for corticosteroid therapy were independently associated with revisits. Fever and age over 48 years were associated with a need for hospitalization.
OBJETIVO: Analizar las revisitas y los factores asociados a la misma en pacientes con diagnóstico de posible COVID-19 dados de alta de un servicio de urgencias hospitalario (SUH). METODO: Estudio observacional, retrospectivo que incluyó pacientes consecutivos que consultaron al SUH en un periodo de 2 meses y fueron diagnosticados de posible de COVID-19. Se analizaron variables clínico-epidemiológicas, tratamiento administrado en urgencias, destino final, revisita al SUH y motivo de esta. Se hizo un análisis comparativo entre ambos grupos (revisita sí/no) y se identificaron factores asociados a la revisita. RESULTADOS: Se incluyeron 2.378 pacientes (edad media 57 años; 49% mujeres). De los pacientes dados de alta (39% del total; n = 925), 170 (20,5%) reconsultaron al SUH, principalmente por persistencia o progresión de síntomas, y 66 (38,8%) precisaron ingreso. Los factores relacionados con la revisita fueron: antecedentes de enfermedad reumatológica [OR: 2,97 (IC 95%: 1,10-7,99, p = 0,03)], síntomas digestivos [OR: 1,73 (IC 95%: 1,14-2,63, p = 0,01)], frecuencia respiratoria $ 20 [OR: 1,03 (IC 95%: 1,0-1,06, p = 0,05)] y haber recibido tratamiento con esteroides en urgencias [OR: 7,78 (IC 95%: 1,77-14,21, p = 0,01)]. Los factores asociados al ingreso en la revisita fueron la edad $ 48 años [OR: 2,57 (IC 95%: 1,42-4,67, p = 0,002)] y presentar fiebre [OR: 4,73 (IC 95%: 1,99-11,27, p = 0,001)]. CONCLUSIONES: Los pacientes con posible COVID-19 menores de 48 años, sin comorbilidad y con signos vitales normales podrían ser dados de alta desde urgencias sin temor a sufrir complicaciones. Los antecedentes de enfermedad reumatológica, fiebre, sintomas digestivos, frecuencia respiratoria $ 20/min o necesidad de tratamiento con esteroides fueron factores independientes de revisita, y la fiebre y edad $ 48 años de necesidad de ingreso.
Assuntos
COVID-19/terapia , Serviço Hospitalar de Emergência , Alta do Paciente/normas , Readmissão do Paciente/estatística & dados numéricos , Adulto , Idoso , COVID-19/complicações , COVID-19/diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
PAM50/Prosigna gene expression-based assay identifies three categorical risk of relapse groups (ROR-low, ROR-intermediate and ROR-high) in post-menopausal patients with estrogen receptor estrogen receptor-positive (ER+)/ HER2-negative (HER2-) early breast cancer. Low risk patients might not need adjuvant chemotherapy since their risk of distant relapse at 10-years is below 10% with endocrine therapy only. In this study, 517 consecutive patients with ER+/HER2- and node-negative disease were evaluated for Ki67 and Prosigna. Most of Luminal A tumors (65.6%) and ROR-low tumors (70.9%) had low Ki67 values (0-10%); however, the percentage of patients with ROR-medium or ROR-high disease within the Ki67 0-10% group was 42.7% (with tumor sizes ≤2 cm) and 33.9% (with tumor sizes > 2 cm). Finally, we found that the optimal Ki67 cutoff for identifying Luminal A or ROR-low tumors was 14%. Ki67 as a surrogate biomarker in identifying Prosigna low-risk outcome patients or Luminal A disease in the clinical setting is unreliable. In the absence of a well-validated prognostic gene expression-based assay, the optimal Ki67 cutoff for identifying low-risk outcome patients or Luminal A disease remains at 14%.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/diagnóstico , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Medição de Risco/métodos , Tamoxifeno/uso terapêutico , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/genética , Quimioterapia Adjuvante , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Incidência , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/genética , Prognóstico , Estudos ProspectivosRESUMO
Currently, limited data exist on the safety of pembrolizumab in patients with metastatic melanoma who have developed severe immune-related adverse events following treatment with ipilimumab. We report a 45-year-old male patient with BRAF-mutant metastatic melanoma who discontinued treatment with ipilimumab due to treatment-related grade 3 colitis and was subsequently treated with the anti-programmed cell death 1 protein (PD-1) antibody pembrolizumab. He has been on treatment with pembrolizumab for more than 20 months with no major toxicities and has achieved an objective partial response, which is ongoing.
Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Colite/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Melanoma/tratamento farmacológico , Antígeno CTLA-4/imunologia , Colite/etiologia , Humanos , Ipilimumab , Masculino , Melanoma/complicações , Melanoma/genética , Pessoa de Meia-Idade , Mutação/genética , Metástase Neoplásica , Receptor de Morte Celular Programada 1/imunologia , Proteínas Proto-Oncogênicas B-raf/genética , Qualidade de Vida , Suspensão de TratamentoRESUMO
Immune checkpoint inhibitors, such as ipilimumab (an anti-CTLA4 antibody), have become a commonly used therapy in cancer. To date, safety data of patients with underlying autoimmune disease is limited. We present a case of a patient with rheumatoid arthritis who was diagnosed of a BRAF-mutant metastatic melanoma. The patient was treated with ipilimumab and presented with high-grade colitis requiring immunosuppressors. Despite of the immune-related adverse event, no exacerbation of the rheumatoid arthritis was observed and the patient achieved a complete response. This case report contributes to the scarce literature on the use of immune checkpoint inhibitors in patients with an underlying autoimmune condition.