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1.
Rev. esp. geriatr. gerontol. (Ed. impr.) ; 55(5): 286-288, sept.-oct. 2020. tab
Artigo em Espanhol | IBECS | ID: ibc-192478

RESUMO

INTRODUCCIÓN: El síndrome de tormenta de citoquinas (STC) es una complicación muy grave de los pacientes con infección por SARS-CoV-2. El tratamiento y la evolución no están bien definidos. Nuestro objetivo es describir sus características clínicas, los tratamientos empleados y su evolución clínica. PACIENTES Y MÉTODO: Estudio retrospectivo observacional de pacientes consecutivos ingresados en el período comprendido entre el 23 de marzo y el 12 de abril de 2020 con infección por SARS-CoV-2 confirmada, con neumonía por estudio radiológico o tomografía de tórax, que cumplían criterios de STC y que recibieron tratamiento. Clasificamos a los pacientes en los que recibieron solo pulsos de glucocorticoides (GC), o pulsos de GC y tocilizumab. Determinamos niveles séricos de ferritina, PCR y dímeros-D. La variable final fue la supervivencia. RESULTADOS: Veintiún pacientes con una edad de 83 años (80-88 años). La ferritina media fue de 1.056 microg/L (317-3.553), la PCR de 115,8mg/dL (22-306) y los dímeros-D de 2,9mg/L (0,45-17,5). Todos los pacientes recibieron pulsos de GC y en 2 casos simultáneamente tocilizumab. El tiempo medio de seguimiento fue de 13,7 días (8-21). La mortalidad global fue del 38,1% (8/21pacientes). Los 2 pacientes que recibieron tocilizumab fallecieron. Los fallecidos presentaron niveles significativamente más elevados de ferritina (1.254 vs. 925microg/L; p = 0,045) y PCR (197,6 vs. 76mg/dL; p = 0,007). Al final del seguimiento se observó una disminución en los parámetros bioquímicos con ferritina de 727microg/L, PCR de 27mg/dl y dímeros-D de 1,18mg/L. En 13/21 pacientes (61,9%) el STC se controló sin necesidad de añadir otros tratamientos. CONCLUSIONES: La mortalidad del STC por SARS-CoV-2 es alta a pesar del tratamiento. Una mayor respuesta inflamatoria se asoció con una mayor mortalidad. Aunque parece que el uso precoz de pulsos de GC puede controlarlo, pudiendo disminuir la necesidad de uso de otros tratamientos, con el diseño del estudio y sus limitaciones, no se puede establecer esta conclusión


INTRODUCTION: Cytokine storm syndrome (CTS) is a serious complication of patients with SARS-CoV-2 infection. Treatment and evolution in octogenarians are not well defiREVned. Our objective is to describe its clinical characteristics, the treatments and its clinical evolution. PATIENTS AND METHOD: Retrospective observational study of consecutive patients admitted in the period between March 23 and April 12, 2020 with confirmed SARS-CoV-2 infection, with pneumonia by radiological study or chest tomography, whith STC criteria and who received treatment. We classified patients as those who received only glucocorticoid (GC) pulses, or GC and tocilizumab pulses. We determined serum levels of ferritin, CRP and D-dimers. The final variable was survival. RESULTS: 21 patients, (80-88 years). The mean ferritin was 1056 microg/L (317-3,553), CRP 115.8mg/dL (22-306) and D-dimers 2.9m/L (0.45-17.5). All patients received GC pulses and in 2 cases simultaneously tocilizumab. The mean follow-up time was 13.7 days (8-21). The overall mortality was 38.1% (8/21 patients). The 2 patients who received tocilizumab died. The deceased had significantly higher levels of ferritin (1,254 vs. 925microg/L; P=.045) and CRP (197.6 vs. 76mg / dL; P=.007). At the end of the follow-up, a decrease in the biochemical parameters was observed with ferritin of 727microg/L, CRP of 27mg/dl and D-dimers of 1.18mg/L. In 13/21 patients (61.9%), the CTS was controlled without the need to add other treatments. CONCLUSIONS: STC mortality from SARS-CoV-2 is high despite treatment. A greater inflammatory response was associated with a higher mortality. Although it seems that the early use of GC pulses could control it, and the use of other treatments such as tocilizumab shouldo be, with the study design and its limitations, this conclusion cannot be stablished


Assuntos
Humanos , Masculino , Feminino , Idoso de 80 Anos ou mais , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Vírus da SARS/patogenicidade , Citocinas/efeitos adversos , Inflamação/fisiopatologia , Glucocorticoides/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos Retrospectivos , Infecções por Coronavirus/epidemiologia , Epidemias , Mediadores da Inflamação/imunologia , Inflamação/imunologia , Ferritinas/efeitos dos fármacos , Linfo-Histiocitose Hemofagocítica/imunologia
2.
Am J Case Rep ; 21: e927812, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: covidwho-811592

RESUMO

BACKGROUND This is a case report of an immunocompromised patient with a history of non-Hodgkin lymphoma and persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who was seronegative and successfully treated with convalescent plasma. CASE REPORT A 63-year-old woman with a past medical history of non-Hodgkin lymphoma in remission while on maintenance therapy with the anti-CD20 monoclonal antibody, obinutuzumab, tested positive for SARS-CoV-2 via nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) testing over 12 weeks and persistently tested seronegative for immunoglobulin G (IgG) antibodies using SARS-CoV-2 IgG chemiluminescent microparticle immunoassay technology. During this time, the patient experienced waxing and waning of symptoms, which included fever, myalgia, and non-productive cough, but never acquired severe respiratory distress. She was admitted to our hospital on illness day 88, and her symptoms resolved after the administration of convalescent plasma. CONCLUSIONS As the understanding of the pathogenesis of SARS-CoV-2 continues to evolve, we can currently only speculate about the occurrence of chronic infection vs. reinfection. The protective role of antibodies and their longevity against SARS-CoV-2 remain unclear. Since humoral immunity has an integral role in SARS-CoV-2 infection, various phase 3 vaccine trials are underway. In the context of this pandemic, the present case demonstrates the challenges in our understanding of testing and treating immunocompromised patients.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Hospedeiro Imunocomprometido , Linfoma não Hodgkin/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Antineoplásicos Imunológicos/administração & dosagem , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/terapia , Feminino , Seguimentos , Humanos , Imunização Passiva/métodos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Pessoa de Meia-Idade , Pandemias , Reação em Cadeia da Polimerase em Tempo Real/métodos , Testes Sorológicos/métodos , Índice de Gravidade de Doença , Resultado do Tratamento
3.
Am J Case Rep ; 21: e927812, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: covidwho-854653

RESUMO

BACKGROUND This is a case report of an immunocompromised patient with a history of non-Hodgkin lymphoma and persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who was seronegative and successfully treated with convalescent plasma. CASE REPORT A 63-year-old woman with a past medical history of non-Hodgkin lymphoma in remission while on maintenance therapy with the anti-CD20 monoclonal antibody, obinutuzumab, tested positive for SARS-CoV-2 via nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) testing over 12 weeks and persistently tested seronegative for immunoglobulin G (IgG) antibodies using SARS-CoV-2 IgG chemiluminescent microparticle immunoassay technology. During this time, the patient experienced waxing and waning of symptoms, which included fever, myalgia, and non-productive cough, but never acquired severe respiratory distress. She was admitted to our hospital on illness day 88, and her symptoms resolved after the administration of convalescent plasma. CONCLUSIONS As the understanding of the pathogenesis of SARS-CoV-2 continues to evolve, we can currently only speculate about the occurrence of chronic infection vs. reinfection. The protective role of antibodies and their longevity against SARS-CoV-2 remain unclear. Since humoral immunity has an integral role in SARS-CoV-2 infection, various phase 3 vaccine trials are underway. In the context of this pandemic, the present case demonstrates the challenges in our understanding of testing and treating immunocompromised patients.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Hospedeiro Imunocomprometido , Linfoma não Hodgkin/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Antineoplásicos Imunológicos/administração & dosagem , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/terapia , Feminino , Seguimentos , Humanos , Imunização Passiva/métodos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Pessoa de Meia-Idade , Pandemias , Reação em Cadeia da Polimerase em Tempo Real/métodos , Testes Sorológicos/métodos , Índice de Gravidade de Doença , Resultado do Tratamento
4.
Lancet Oncol ; 21(10): 1283-1295, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33002436

RESUMO

BACKGROUND: HER2-positive metastatic breast cancer is incurable and new treatments are needed. Addition of atezolizumab to trastuzumab emtansine might potentiate anticancer immunity and enhance the HER2-targeted cytotoxic activity of trastuzumab emtansine. We aimed to test this combination in HER2-positive advanced breast cancer that had progressed after previous treatment with trastuzumab and a taxane. METHODS: The KATE2 study is a randomised, double-blind, placebo-controlled, phase 2 study at 68 centres from nine countries across Asia, Australia, North America, and western Europe. Eligible patients were adults (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and centrally confirmed, measurable, HER2-positive advanced breast cancer previously treated with trastuzumab and a taxane. Patients were randomly assigned (2:1) either trastuzumab emtansine (3·6 mg/kg of bodyweight) plus atezolizumab (1200 mg) or trastuzumab emtansine plus placebo; all study drugs were administered by intravenous infusion every 3 weeks. Randomisation was done via an interactive voice and web response system using a permuted block scheme (block size of six) and was stratified by PD-L1 status, world region, and liver metastases. Patients, investigators, and study team members were masked to treatment allocation. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02924883, and the study has been completed. FINDINGS: Between Sept 26, 2016, and Aug 7, 2017, 330 patients were screened for the study, of whom 202 were randomly allocated either atezolizumab (n=133) or placebo (n=69). At the recommendation of the independent data monitoring committee, treatment assignment was unmasked on Dec 11, 2017, due to futility and the numerically higher frequency of adverse events among patients assigned atezolizumab. This date was set as the clinical cutoff for the primary analysis. Median follow-up was 8·5 months (IQR 6·1-11·5) for patients assigned atezolizumab and 8·4 months (5·3-11·1) for those assigned placebo. Median progression-free survival was 8·2 months (95% CI 5·8-10·7) for patients assigned atezolizumab versus 6·8 months (4·0-11·1) for those assigned placebo (stratified hazard ratio 0·82, 95% CI 0·55-1·23; p=0·33). The most common grade 3 or worse adverse events were thrombocytopenia (17 [13%] among 132 patients who received atezolizumab vs three [4%] among 68 who received placebo), increased aspartate aminotransferase (11 [8%] vs two [3%]), anaemia (seven [5%] vs 0), neutropenia (six [5%] vs three [4%]), and increased alanine aminotransferase (six [5%] vs two [3%]). Serious adverse events occurred in 43 (33%) of 132 patients who received atezolizumab and 13 (19%) of 68 patients who received placebo. One patient who received atezolizumab died due to a treatment-related adverse event (haemophagocytic syndrome). INTERPRETATION: Addition of atezolizumab to trastuzumab emtansine did not show a clinically meaningful improvement in progression-free survival and was associated with more adverse events. Further study of trastuzumab emtansine plus atezolizumab is warranted in a subpopulation of patients with PD-L1-positive, HER2-positive advanced breast cancer. FUNDING: F Hoffman-La Roche.


Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/patologia , Método Duplo-Cego , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/metabolismo , Análise de Sobrevida , Resultado do Tratamento
5.
Am J Case Rep ; 21: e927812, 2020 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-33009361

RESUMO

BACKGROUND This is a case report of an immunocompromised patient with a history of non-Hodgkin lymphoma and persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection who was seronegative and successfully treated with convalescent plasma. CASE REPORT A 63-year-old woman with a past medical history of non-Hodgkin lymphoma in remission while on maintenance therapy with the anti-CD20 monoclonal antibody, obinutuzumab, tested positive for SARS-CoV-2 via nasopharyngeal reverse transcription polymerase chain reaction (RT-PCR) testing over 12 weeks and persistently tested seronegative for immunoglobulin G (IgG) antibodies using SARS-CoV-2 IgG chemiluminescent microparticle immunoassay technology. During this time, the patient experienced waxing and waning of symptoms, which included fever, myalgia, and non-productive cough, but never acquired severe respiratory distress. She was admitted to our hospital on illness day 88, and her symptoms resolved after the administration of convalescent plasma. CONCLUSIONS As the understanding of the pathogenesis of SARS-CoV-2 continues to evolve, we can currently only speculate about the occurrence of chronic infection vs. reinfection. The protective role of antibodies and their longevity against SARS-CoV-2 remain unclear. Since humoral immunity has an integral role in SARS-CoV-2 infection, various phase 3 vaccine trials are underway. In the context of this pandemic, the present case demonstrates the challenges in our understanding of testing and treating immunocompromised patients.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Hospedeiro Imunocomprometido , Linfoma não Hodgkin/imunologia , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Antineoplásicos Imunológicos/administração & dosagem , Técnicas de Laboratório Clínico/métodos , Infecções por Coronavirus/terapia , Feminino , Seguimentos , Humanos , Imunização Passiva/métodos , Linfoma não Hodgkin/complicações , Linfoma não Hodgkin/tratamento farmacológico , Pessoa de Meia-Idade , Pandemias , Reação em Cadeia da Polimerase em Tempo Real/métodos , Testes Sorológicos/métodos , Índice de Gravidade de Doença , Resultado do Tratamento
6.
Monaldi Arch Chest Dis ; 90(4)2020 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-33059413

RESUMO

Knowledge of treatment regimens and outcomes for novel coronavirus disease 2019 (COVID-19) is evolving. Recent studies have reported mortality rates ranging from 39-50% among hospitalized patients with COVID-19. We report our experience ofmanagement and outcomes of hospitalized patients with COVID-19 at a large tertiary-care center in Midwestern United States. Of 658 patients presenting to our tertiary care center, 217 needed hospitalization, majority (77%) of whom were severely sick requiring admission to the intensive care unit (ICU). All received corticosteroids, and 78% of the patients received tocilizumab. More than two-thirds of the patients received anticoagulation and 80% of patients in the ICU had prone-positioning. The median duration of hospitalization was 12 days (interquartile range, 8 to16), median duration of intensive care unit stay was 7 days (interquartile range, 5 to 9) and requirement of mechanical ventilation was 6 days (interquartile range, 5 to 8) in our cohort. Of the 217 patients, 27 died (12% mortality). The majority of our patients received corticosteroids, tocilizumab, anticoagulation and prone positioning. While higher mortality rates of >30% have been reported in various studies among hospitalized patients with COVID-19, the majority of hospitalized patients in our cohort survived with a low mortality rate. The majority of our patients received corticosteroids, tocilizumab, anticoagulation and prone positioning. While higher mortality rates of >30% have been reported in various studies among hospitalized patients with COVID-19, the majority of hospitalized patients in our cohort survived with a low mortality rate.


Assuntos
Betacoronavirus , Infecções por Coronavirus/terapia , Cuidados Críticos , Hospitalização , Pneumonia Viral/terapia , Atenção Terciária à Saúde , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticoagulantes/uso terapêutico , Antivirais/uso terapêutico , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/epidemiologia , Glucocorticoides/uso terapêutico , Humanos , Imunização Passiva , Meio-Oeste dos Estados Unidos , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/epidemiologia , Respiração Artificial , Estudos Retrospectivos , Centros de Atenção Terciária
7.
Isr Med Assoc J ; 9(22): 491-497, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954695

RESUMO

BACKGROUND: Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA. OBJECTIVES: To evaluate SC tocilizumab in a real-life clinical setting. METHODS: Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed. RESULTS: Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively. CONCLUSIONS: The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Qualidade de Vida , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Antirreumáticos/efeitos adversos , Artrite Reumatoide/fisiopatologia , Quimioterapia Combinada , Feminino , Humanos , Injeções Subcutâneas , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do Tratamento
8.
Isr Med Assoc J ; 9(22): 498-502, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32954696

RESUMO

BACKGROUND: Progress in the treatment of breast cancer has led to substantial improvement in survival, but at the cost of increased side effects, with cardiotoxicity being the most significant one. The commonly used definition is cancer therapeutics-related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction reduction of > 10%, to a value below 53%. Recent studies have implied that the incidence of CTRCD among patients with breast cancer is decreasing due to lower doses of anthracyclines and low association to trastuzumab and pertuzumab treatment. OBJECTIVES: To evaluate the prevalence of CTRCD among patients with active breast cancer and to identify significant associates for its development. METHODS: Data were collected as part of the Israel Cardio-Oncology Registry, which enrolls all patients who are evaluated at the cardio-oncology clinic at our institution. Patients were divided to two groups: CTRCD and no-CTRCD. RESULTS: Among 103 consecutive patients, five (5%) developed CTRCD. There were no significant differences in the baseline cardiac risk factors between the groups. Significant correlations of CTRCD included treatment with trastuzumab (P = 0.001) or pertuzumab (P < 0.001), lower baseline global longitudinal strain (GLS) (P = 0.016), increased left ventricular end systolic diameter (P < 0.001), and lower e' septal (P < 0.001). CONCLUSIONS: CTRCD is an important concern among patients with active breast cancer, regardless of baseline risk factors, and is associated with trastuzumab and pertuzumab treatment. Early GLS evaluation may contribute to risk stratification and allow deployment of cardioprotective treatment.


Assuntos
Antineoplásicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Cardiotoxicidade/epidemiologia , Disfunção Ventricular Esquerda/epidemiologia , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/administração & dosagem , Cardiotoxicidade/etiologia , Feminino , Humanos , Israel , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Disfunção Ventricular Esquerda/induzido quimicamente
11.
Lancet Oncol ; 21(9): 1188-1200, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32888452

RESUMO

BACKGROUND: Venetoclax plus obinutuzumab has been established as a fixed-duration treatment regimen for patients with chronic lymphocytic leukaemia. We compared the long-term efficacy after treatment cessation of the combination of venetoclax plus obinutuzumab with chlorambucil plus obinutuzumab in patients with previously untreated chronic lymphocytic leukaemia. METHODS: CLL14 is a multicentre, randomised, open-label, phase 3 trial done at 196 sites in 21 countries. Eligible patients were aged 18 years or older, had untreated chronic lymphocytic leukaemia, and coexisting conditions with a cumulative illness rating scale greater than 6, a creatinine clearance of 30-69 mL/min, or both. Patients were randomly assigned (1:1) via a web and voicemail system with allocation concealment and based on a computer-generated randomisation schedule with a block size of six and stratified by Binet stage and geographical region. Patients received either venetoclax plus obinutuzumab (oral venetoclax initiated on day 22 of cycle 1 [28-day cycles], with a 5-week dose ramp-up [20 mg, 50 mg, 100 mg, and 200 mg, then 400 mg daily for 1 week], thereafter continuing at 400 mg daily until completion of cycle 12; combined with intravenous obinutuzumab for six cycles starting with 100 mg on day 1 and 900 mg on day 2 [or 1000 mg on day 1], 1000 mg on days 8 and day 15 of cycle 1, and subsequently 1000 mg on day 1 of cycles 2 through 6) or chlorambucil plus obinutuzumab (oral chlorambucil at 0·5 mg/kg bodyweight on days 1 and 15 of each cycle for 12 cycles combined with the same obinutuzumab regimen). The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. Patient enrolment is complete, and the study is registered with ClinicalTrails.gov, NCT02242942. FINDINGS: Between Aug 7, 2015, and Aug 4, 2016, 432 patients were enrolled and randomly assigned to receive either venetoclax plus obinutuzumab (n=216) or chlorambucil plus obinutuzumab (n=216). All patients had been off treatment for at least 24 months at data collection. At a median follow-up of 39·6 months (IQR 36·8-43·0), patients given venetoclax plus obinutuzumab had a significantly longer progression-free survival than did patients given chlorambucil plus obinutuzumab (HR 0·31, 95% CI 0·22-0·44; p<0·0001). Median progression-free survival was not reached (95% CI not estimable to not estimable) in the venetoclax plus obinutuzumab group vs 35·6 months (33·7-40·7) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse event in both groups was neutropenia (112 [53%] of 212 patients in the venetoclax plus obinutuzumab group versus 102 [48%] of 214 patients in the chlorambucil plus obinutuzumab group). Serious adverse events occurred in 115 (54%) of 212 patients in the venetoclax plus obinutuzumab group and 95 (44%) of 214 patients in the chlorambucil plus obinutuzumab group. Venetoclax or chlorambucil treatment-related deaths were reported in one (1%) of 212 patients in the venetoclax plus obinutuzumab group (n=1 sepsis) and two (1%) of 214 patients in the chlorambucil plus obinutuzumab group (n=1 septic shock, n=1 metastatic skin squamous carcinoma). INTERPRETATION: 2 years after treatment cessation, venetoclax plus obinutuzumab continues to significantly improve progression-survival compared with chlorambucil plus obinutuzumab, thereby providing a limited duration treatment option for patients with previously untreated chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche and AbbVie.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Clorambucila/administração & dosagem , Leucemia Linfocítica Crônica de Células B/tratamento farmacológico , Sulfonamidas/administração & dosagem , Adolescente , Adulto , Idoso , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Compostos Bicíclicos Heterocíclicos com Pontes/efeitos adversos , Clorambucila/efeitos adversos , Feminino , Seguimentos , Humanos , Leucemia Linfocítica Crônica de Células B/patologia , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Sulfonamidas/efeitos adversos , Resultado do Tratamento
13.
Int J Rheum Dis ; 23(8): 1030-1039, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32881350

RESUMO

AIM: To describe the first Australian cases of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV2) disease (COVID-19) pneumonia treated with the interleukin-6 receptor antagonist tocilizumab. METHODS: Retrospective, open-label, real-world, uncontrolled, single-arm case series conducted in 2 tertiary hospitals in NSW, Australia and 1 tertiary hospital in Victoria, Australia. Five adult male patients aged between 46 and 74 years with type 1 respiratory failure due to COVID-19 pneumonia requiring intensive care unit (ICU) admission and biochemical evidence of systemic hyperinflammation (C-reactive protein greater than 100 mg/L; ferritin greater than 700 µg/L) were administered variable-dose tocilizumab. RESULTS: At between 13 and 26 days follow-up, all patients are alive and have been discharged from ICU. Two patients have been discharged home. Two patients avoided endotracheal intubation. Oxygen therapy has been ceased in three patients. Four adverse events potentially associated with tocilizumab therapy occurred in three patients: ventilator-associated pneumonia, bacteremia associated with central venous catheterization, myositis and hepatitis. All patients received broad-spectrum antibiotics, 4 received corticosteroids and 2 received both lopinavir/ritonavir and hydroxychloroquine. The time from first tocilizumab administration to improvement in ventilation, defined as a 25% reduction in fraction of inspired oxygen required to maintain peripheral oxygen saturation greater than 92%, ranged from 7 hours to 4.6 days. CONCLUSIONS: Tocilizumab use was associated with favorable clinical outcome in our patients. We recommend tocilizumab be included in randomized controlled trials of treatment for patients with severe COVID-19 pneumonia, and be considered for compassionate use in such patients pending the results of these trials.


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Idoso , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/virologia , Interações entre Hospedeiro e Microrganismos , Humanos , Masculino , Pessoa de Meia-Idade , New South Wales , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/virologia , Estudos Retrospectivos , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Vitória
14.
Trials ; 21(1): 758, 2020 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-32883328

RESUMO

OBJECTIVES: Tocilizumab is a humanized monoclonal antibody which targets and inhibits interleukin-6 (IL-6) and has demonstrated efficacy in treating diseases associated with hyper-inflammation. Data are suggestive of tocilizumab as a potential treatment for patients with COVID-19 infection. The aim of this study is to determine the safety and efficacy of standard dose versus low dose tocilizumab in adults with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation on time to intubation, non-invasive ventilation and/or all-cause mortality. TRIAL DESIGN: This trial is a phase 2, open label, two-stage, multicentre, randomised trial. PARTICIPANTS: Adult subjects with severe, non-critical, PCR-confirmed COVID-19 infection with evidence of progressive decline in respiratory function and evolving systemic inflammation requiring admission to hospital at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Inclusion criteria Aged 18 years or older. Confirmed SARS-CoV2 infection (as defined by positive PCR). Evidence of hyper inflammatory state as evidenced by at least three of the following: Documented temperature >38°C in the past 48 hours, IL6 >40 pg/ml, or in its absence D-dimer >1.5 µgFEU /ml, Elevated CRP (>100mg/L) and/or a three-fold increase since presentation, Elevated ferritin X5 ULN, Elevated LDH (above the ULN), Elevated fibrinogen (above the ULN). Pulmonary infiltrates on chest imaging. Moderate to severe respiratory failure as defined by PaO2/FiO2≤300mmHg. INTERVENTION AND COMPARATOR: Intervention for participants in this trial is SOC plus Tocilizumab compared to SOC alone (comparator). For Stage 1, following randomisation, subjects will receive either (Arm 1) SOC alone or (Arm 2) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes. Once stage 1 has fully recruited, subsequent participants will be enrolled directly into Stage 2 and receive either (Arm 1) SOC plus Tocilizumab (standard single dose - 8mg/kg, infused over 60 minutes or (Arm 2) SOC plus Tocilizumab (standard single dose - 4mg/kg, infused over 60 minutes). MAIN OUTCOMES: The primary endpoint for this study is the time to a composite primary endpoint of progression to intubation and ventilation, non-invasive ventilation or death within 28 days post randomisation. RANDOMISATION: Eligible patients will be randomised (1:1) using a central register. Randomisation will be performed through an interactive, web-based electronic data capturing database. In stage 1, eligible participants will be randomised (1:1) to (Arm 1) SOC alone or to (Arm 2) SOC with single dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. In stage 2, eligible participants will be randomised (1:1) to receive either (Arm 1) single, standard dose (8mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes or (Arm 2) reduced dose (4mg/kg, maximum 800mg) intravenous tocilizumab infused over 60 minutes. BLINDING: This study is open label. The study will not be blinded to investigators, subjects, or medical or nursing staff. The trial statistician will be blinded for data analysis and will be kept unaware of treatment group assignments. To facilitate this, the randomisation schedule will be drawn up by an independent statistician and objective criteria were defined for the primary outcome to minimize potential bias. NUMBERS TO BE RANDOMISED: In stage 1, 90 subjects will be randomised 1:1, 45 to SOC and 45 subjects to SOC plus Tocilizumab (8mg/kg, infused over 60 minutes). In stage 2, sample size calculation for the dose evaluation stage will use data generated from stage 1 using the same primary endpoint as in stage 1. TRIAL STATUS: The COVIRL002 trial (Protocol version 1.4, 13th May 2020) commenced in May 2020 at St. Vincent's University Hospital and Mater Misericordiae University Hospital, Dublin, Ireland. Recruitment is proceeding with the aim to achieve the target sample size on or before April 2021. TRIAL REGISTRATION: COVIRL002 was registered 25 June 2020 under EudraCT number: 2020-001767-86 and Protocol identification: UCDCRC/20/02. FULL PROTOCOL: The full protocol for COVIRL002 is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol. The study protocol has been reported in accordance with the Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).


Assuntos
Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Betacoronavirus/patogenicidade , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Progressão da Doença , Interações entre Hospedeiro e Microrganismos , Humanos , Intubação Intratraqueal , Irlanda , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
15.
J UOEH ; 42(3): 261-266, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879190

RESUMO

Radiation recall pneumonitis is a phenomenon in which a recall-triggering drug induces an acute inflammatory reaction in the lungs, corresponding to a previously irradiated area. Radiation recall reactions have been reported to occur following treatments with various cytotoxic anticancer agents and molecular-targeting drugs; however, only a few reports have described immune checkpoint inhibitor-induced radiation recall pneumonitis. We report a case of radiation recall pneumonitis induced by pembrolizumab in a patient with the postoperative local recurrence of non-small cell lung cancer. This case demonstrated that pembrolizumab might cause severe radiation recall pneumonitis, even after typical radiation pneumonitis has been resolved.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos/efeitos adversos , Doenças Assintomáticas , Carcinoma Pulmonar de Células não Pequenas/terapia , Neoplasias Pulmonares/terapia , Pneumonite por Radiação/etiologia , Radioterapia/efeitos adversos , Terapia Combinada , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/radioterapia
20.
Am J Case Rep ; 21: e927418, 2020 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-32917848

RESUMO

BACKGROUND Patients receiving immunosuppressive therapies might be more susceptible to COVID-19. Conversely, an exaggerated inflammatory response to the SARS-CoV-2 infection might be blunted by certain forms of immunosuppression, which could be protective. Indeed, there are data from animal models demonstrating that complement may be a part of the pathophysiology of coronavirus infections. There is also evidence from an autopsy series demonstrating complement deposition in the lungs of patients with COVID-19. This raises the question of whether patients on anti-complement therapy could be protected from COVID-19. CASE REPORT Case 1 is a 39-year-old woman with an approximately 20-year history of paroxysmal nocturnal hemoglobinuria (PNH), who had recently been switched from treatment with eculizumab to ravulizumab prior to SARS-CoV-2 infection. Case 2 is a 54-year-old woman with a cadaveric renal transplant for lupus nephritis, complicated by thrombotic microangiopathy, who was maintained on eculizumab, which she started several months before she developed the SARS-CoV-2 infection. Case 3 is a 60-year-old woman with a 14-year history of PNH, who had been treated with eculizumab since 2012, and was diagnosed with COVID-19 at the time of her scheduled infusion. All 3 patients had a relatively mild course of COVID-19. CONCLUSIONS We see no evidence of increased susceptibility to SARS-CoV-2 in these patients on anti-complement therapy, which might actually have accounted for the mild course of infection. The effect of anti-complement therapy on COVID-19 disease needs to be determined in clinical trials.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Complemento C5/metabolismo , Infecções por Coronavirus/complicações , Hemoglobinúria Paroxística/tratamento farmacológico , Pneumonia Viral/complicações , Microangiopatias Trombóticas/tratamento farmacológico , Adulto , Betacoronavirus , Complemento C5/efeitos dos fármacos , Complemento C5/imunologia , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/epidemiologia , Feminino , Hemoglobinúria Paroxística/complicações , Hemoglobinúria Paroxística/imunologia , Humanos , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia , Microangiopatias Trombóticas/complicações , Microangiopatias Trombóticas/imunologia
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