RESUMO
BACKGROUND: The prognosis for patients with relapsed and/or refractory (R/R) non-Hodgkin's lymphoma (NHL) or acute lymphoblastic leukaemia (ALL) remains poor, with existing treatments having significant side effects. Developed for the treatment of these cancers, AFM11 is a tetravalent, bispecific humanised recombinant antibody construct (TandAb®) designed to bind to human CD19 and CD3 and lead to the activation of T cells inducing apoptosis and killing of malignant B cells. METHODS: Two open-label, multicentre, dose-escalation phase 1 studies evaluated the safety, pharmacokinetics and activity of AFM11 in patients with R/R CD19-positive B cell NHL (AFM11-101) and in patients with CD19 + B-precursor Philadelphia-chromosome negative ALL (AFM11-102). Adverse events (AEs) were assessed and recorded; imaging (NHL) or bone marrow assessment (ALL) were used to evaluate response. Additional pharmacodynamic assays undertaken included cytokine release analysis and B-cell and T-cell depletion. RESULTS: In AFM11-101, 16 patients with R/R NHL received AFM11 in five different dose cohorts. Of which, 14 experienced drug-related treatment-emergent AEs (TEAEs) [including five serious AEs (SAEs)], five patients experienced dose-limiting toxicity (DLT) and ten patients discontinued the study. The high number of neurological events led to a decrease in infusion frequency during the study. No objective response to treatment was observed. In AFM11-102, 17 patients with R/R ALL received AFM11 in six different dose cohorts. Thirteen patients experienced drug-related TEAEs (including four SAEs), DLTs occurred in two patients and five patients discontinued the study. An objective response was recorded in three patients. The maximum tolerated dose could not be determined in either study due to early termination. CONCLUSIONS: AFM11 treatment was associated with frequent neurological adverse reactions that were severe in some patients. In ALL, some signs of activity, albeit short-lived, were observed whereas no activity was observed in patients with NHL; therefore, further clinical development was terminated. TRIAL REGISTRATION: NCT02106091 . Safety Study to Assess AFM11 in Patients With Relapsed and/or Refractory CD19 Positive B-cell NHL. Registered April 2014. NCT02848911 . Safety Study to Assess AFM11 in Patients With Relapsed or Refractory Adult B-precursor ALL. Registered July 2016.
Assuntos
Anticorpos Biespecíficos , Antineoplásicos , Linfoma não Hodgkin , Adulto , Humanos , Anticorpos Biespecíficos/farmacologia , Anticorpos Biespecíficos/uso terapêutico , Antineoplásicos/efeitos adversos , Citocinas , Linfoma não Hodgkin/tratamento farmacológico , Linfoma não Hodgkin/patologia , Recidiva Local de Neoplasia/tratamento farmacológico , Linfócitos TRESUMO
In relapsed/refractory Hodgkin lymphoma (R/R HL), immunotherapies such as the anti-programmed death-1 inhibitor pembrolizumab have demonstrated efficacy as monotherapy and are playing an increasingly prominent role in treatment. The CD30/CD16A-bispecific antibody AFM13 is an innate immune cell engager, a first-in-class, tetravalent antibody, designed to create a bridge between CD30 on HL cells and the CD16A receptor on natural killer cells and macrophages, to induce tumor cell killing. Early studies of AFM13 have demonstrated signs of efficacy as monotherapy for patients with R/R HL and the combination of AFM13 with pembrolizumab represents a rational new treatment modality. Here, we describe a phase 1b, dose-escalation study to assess the safety and preliminary efficacy of AFM13 in combination with pembrolizumab in patients with R/R HL. The primary objective was estimating the maximum tolerated dose; the secondary objectives were to assess safety, tolerability, antitumor efficacy, pharmacokinetics, and pharmacodynamics. In this heavily pretreated patient population, treatment with the combination of AFM13 and pembrolizumab was generally well tolerated, with similar safety profiles compared to the known profiles of each agent alone. The combination of AFM13 with pembrolizumab demonstrated an objective response rate of 88% at the highest treatment dose, with an 83% overall response rate for the overall population. Pharmacokinetic assessment of AFM13 in the combination setting revealed a half-life of up to 20.6 hours. This proof-of-concept study holds promise as a novel immunotherapy combination worthy of further investigation. This phase 1b study was registered at www.clinicaltrials.gov as NCT02665650.
Assuntos
Antígenos de Neoplasias/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Imunoterapia , Antígeno Ki-1/antagonistas & inibidores , Receptores de IgG/antagonistas & inibidores , Adolescente , Adulto , Idoso , Anticorpos Biespecíficos/administração & dosagem , Anticorpos Biespecíficos/efeitos adversos , Anticorpos Biespecíficos/farmacocinética , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Terapia Combinada , Relação Dose-Resposta Imunológica , Feminino , Meia-Vida , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/terapia , Humanos , Imunidade Inata/efeitos dos fármacos , Antígeno Ki-1/imunologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Receptores de IgG/imunologia , Recidiva , Transplante Autólogo , Adulto JovemRESUMO
BACKGROUND AND OBJECTIVE: CobraPLUS and Cookgas air-Q are supraglottic airways expected to allow safe ventilation as well as reliable blind intubation. In a prospective, controlled trial, we hypothesised that quality of ventilation and success rate of blind endotracheal intubation of these new devices would be superior to the Fastrach intubating laryngeal mask airway (ILMA). When blind intubation failed the quality of fibrescope-guided intubation was investigated. To allow identification of those patients in whom blind intubation would be difficult, we investigated the predictive value of currently used predictors for ease of endotracheal intubation. METHODS: One hundred and eighty adult patients with documented BMI, Mallampati score, Cormack-Lehane classification, interincisor gap and thyromental distance were randomised into three groups according to the device used. Ventilation conditions were rated as excellent, good or difficult. When blind intubation failed, fibrescope-guided intubation conditions were rated as well. Statistical analysis was performed by a χ-test. RESULTS: The quality of ventilation was excellent for all devices. Three patients in the CobraPLUS group and two patients in the ILMA and the Cookgas groups needed a slight reposition. Blind intubation through the CPLA was successful in 47%, through the Cookgas in 57%, whereas the Fastrach group had a success rate of 95%. Fibreoptic intubation was possible in all but one patient. None of the registered scores and measures allowed prediction of difficult blind intubation. CONCLUSION: All devices appeared to be safe airways. The Fastrach ILMA proved to be a reliable facilitator for blind intubation. CobraPLUS and Cookgas air-Q allowed an easy fibrescopic intubation. Failed blind intubations could not be predicted by the used parameters.
Assuntos
Intubação Intratraqueal/métodos , Máscaras Laríngeas , Respiração Artificial/normas , Adulto , Índice de Massa Corporal , Desenho de Equipamento , Feminino , Tecnologia de Fibra Óptica , Humanos , Intubação Intratraqueal/efeitos adversos , Intubação Intratraqueal/instrumentação , Masculino , Estudos Prospectivos , Respiração Artificial/métodosRESUMO
Atrial fibrillation (AF) following cardiac surgery is an important factor contributing to postoperative morbidity. Transvenous, intracardial cardioversion (TIC) has been shown to be effective in the treatment of chronic AF, but is an invasive and cost-intensive procedure. However, TIC would definitely be a beneficial approach if recurrence of AF following TIC is low and pharmacological treatment could be avoided. Thus, we hypothesised that TIC would be superior to conventional treatment with amiodarone with respect to the conversion rate and recurrence of AF. We compared TIC and conventional amiodarone therapy in a prospective, randomised and controlled trial in patients who developed AF following cardiac surgery. Twenty-three patients developed AF out of a total of 76 patients who gave written informed consent. Eighteen of these AF patients could be randomised into two equally sized groups to receive either an ALERT pulmonary artery catheter and TIC, or a standard pulmonary artery catheter and treatment with amiodarone. Haemodynamic parameters were registered before intervention to exclude pulmonary hypertension or fluid overload. Rates of cardioversion were compared by a Likelyhood ratio test. Out of the nine ALERT patients, AF in five cases converted to sinus rhythm (SR) with a median of two shocks (6 J). After 24 hours however, only two patients remained in sinus rhythm. On the other hand, six of the nine patients treated with amiodarone were still in SR after 24 hours. Whereas no difference was detectable in the conversion rate, persistence of SR following TIC was low. Thus, TIC without antiarrhythmic treatment is not recommendable for the treatment of postoperative AF.
Assuntos
Fibrilação Atrial/etiologia , Fibrilação Atrial/terapia , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Cardioversão Elétrica/métodos , Idoso , Idoso de 80 Anos ou mais , Amiodarona/uso terapêutico , Antiarrítmicos/uso terapêutico , Cateterismo de Swan-Ganz , Cardioversão Elétrica/estatística & dados numéricos , Feminino , Humanos , Funções Verossimilhança , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos Prospectivos , Resultado do TratamentoRESUMO
OBJECTIVE: To evaluate the interaction of recruitment maneuvers and prone positioning on gas exchange and venous admixture in patients with early extrapulmonary acute respiratory distress syndrome ventilated with high levels of positive end-expiratory pressure. We hypothesized that a sustained inflation performed after 6 hrs of prone positioning would induce sustained improvement in oxygenation (Pao2/Fio2) and venous admixture. DESIGN: Prospective, interventional study. SETTING: Tertiary care, postoperative intensive care unit. PATIENTS: Fifteen patients with early extrapulmonary acute respiratory distress syndrome. INTERVENTIONS: After 6 hrs of prone positioning, a sustained inflation was performed with 50 cm H2O maintained for 30 secs. Data were recorded in supine position, after 6 hrs of prone positioning, at 3, 30, and 180 mins following the sustained inflation. MEASUREMENTS AND MAIN RESULTS: A response to prone positioning was observed in nine of 15 patients leading to an improvement of Pao2/Fio2 (147 +/- 37 torr vs. 225 +/- 77 torr, p = .005) and venous admixture (35.4 +/- 8.3% vs. 28.9 +/- 9.8%, p = .001). Six patients did not respond to prone positioning. Following the sustained inflation, the responders to prone positioning showed a further increase of Pao2/Fio2 and decrease of venous admixture at 3 mins (Pao2/Fio2, 225 +/- 77 torr vs. 368 +/- 90 torr, p = .018; venous admixture, 28.9 +/- 9.8% vs. 18.9 +/- 6.7%, p = .05). In all six nonresponders to prone positioning, an improvement of Pao2/Fio2 and venous admixture occurred at 3 mins following the sustained inflation (128 +/- 18 torr vs. 277 +/- 59 torr, p = .03; venous admixture, 34.2 +/- 6.0% vs. 23.8 +/- 6.3%, p = .05). The beneficial effects of the sustained inflation remained significantly elevated over 3 hrs in responders and nonresponders to prone positioning. CONCLUSION: In patients with early extrapulmonary acute respiratory distress syndrome, a sustained inflation performed after 6 hrs of prone positioning induced further and sustained improvement of oxygenation and venous admixture in both responders and nonresponders to prone positioning.
Assuntos
Cuidados Críticos/métodos , Oxigênio/sangue , Respiração com Pressão Positiva/métodos , Decúbito Ventral/fisiologia , Troca Gasosa Pulmonar/fisiologia , Síndrome do Desconforto Respiratório/terapia , Adulto , Idoso , Resistência das Vias Respiratórias/fisiologia , Feminino , Humanos , Pressão Hidrostática , Complacência Pulmonar/fisiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Alvéolos Pulmonares/fisiopatologia , Síndrome do Desconforto Respiratório/fisiopatologia , Resultado do TratamentoRESUMO
BACKGROUND: Recruitment maneuvers performed in early adult respiratory distress syndrome remain a matter of dispute in patients ventilated with low tidal volumes and high levels of positive end-expiratory pressure (PEEP). In this prospective, randomized controlled study the authors evaluated the impact of recruitment maneuvers after a PEEP trial on oxygenation and venous admixture (Qs/Qt) in patients with early extrapulmonary adult respiratory distress syndrome. METHODS: After a PEEP trial 30 consecutive patients ventilated with low tidal volumes and high levels of PEEP were randomly assigned to either undergo a recruitment maneuver or not. Data were recorded at baseline, 3 min after the recruitment maneuver, and 30 min after baseline. Recruitment maneuvers were performed with a sustained inflation of 50 cm H2O maintained for 30 s. RESULTS: Compared with baseline the ratio of the arterial oxygen partial pressure to the fraction of inspired oxygen (Pao2/Fio2) and Qs/Qt improved significantly at 3 min after the recruitment maneuver (Pao2/Fio2, 139 +/- 46 mm Hg versus 246 +/- 111 mm Hg, P < 0.001; Qs/Qt, 30.8 +/- 5.8% versus 21.5 +/- 9.7%, P < 0.005), but baseline values were reached again within 30 min. No significant differences in Pao2/Fio2 and Qs/Qt were detected between the recruitment maneuver group and the control group at baseline and after 30 min (recruitment maneuver group [n = 15]: Pao2/Fio2, 139 +/- 46 mm Hg versus 138 +/- 39 mm Hg; Qs/Qt, 30.8 +/- 5.8% versus 29.2 +/- 7.4%; control group: [n = 15]: Pao2/Fio2, 145 +/- 33 mm Hg versus 155 +/- 52 mm Hg; Qs/Qt, 30.2 +/- 8.5% versus 28.1 +/- 5.4%). CONCLUSION: In patients with early extrapulmonary adult respiratory distress syndrome who underwent a PEEP trial, recruitment maneuvers failed to induce a sustained improvement of oxygenation and venous admixture.
Assuntos
Respiração com Pressão Positiva , Síndrome do Desconforto Respiratório/terapia , Idoso , Gasometria , Método Duplo-Cego , Eletrocardiografia , Feminino , Hemodinâmica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Monitorização Intraoperatória , Oxigênio/sangue , Estudos Prospectivos , Troca Gasosa Pulmonar , Síndrome do Desconforto Respiratório/fisiopatologia , Volume de Ventilação Pulmonar/fisiologiaRESUMO
UNLABELLED: We report the occurrence of an intraoperative left atrial hematoma during coronary artery bypass grafting surgery. Echocardiography proved to be of great help in diagnosis and monitoring of this patient. After severe hemodynamic impairment the patient recovered and could be transferred on postoperative day eight. Follow-up examination showed no signs of atrial pathologies. Differential diagnosis and echocardiographic findings are discussed. IMPLICATIONS: The authors report the utility of transesophageal echocardiography for diagnosis and management of an intramural left atrial hematoma during coronary artery surgery.
Assuntos
Ponte de Artéria Coronária/efeitos adversos , Hematoma/etiologia , Complicações Pós-Operatórias/patologia , Idoso , Ecocardiografia Transesofagiana , Átrios do Coração/patologia , Hematoma/diagnóstico por imagem , Humanos , Masculino , Monitorização IntraoperatóriaRESUMO
OBJECTIVE: This study investigated the predictive value of a decrease in monocyte HLA-DR expression as an early marker for postoperative SIRS and septic complications. We hypothesized that decreased HLA-DR levels in the first 24 h after cardiac surgery is not related to postoperative SIRS/sepsis. We also compared HLA-DR levels of patients with postoperative complications to those with an uncomplicated course. DESIGN AND SETTING: Prospective observational study in a tertiary care postoperative intensive care unit. PATIENTS: Eighty five consecutive patients undergoing cardiac surgery. MEASUREMENTS AND RESULTS: Expression of HLA-DR on monocytes was analyzed by flow cytometry using a new quantitative and well standardized technique. Arterial blood samples were collected before induction of anesthesia, immediately after admission to the ICU, and on the first postoperative day. Postoperative HLA-DR expression was significantly decreased in all patients. There were no significant differences in HLA-DR expression during the first 24 h after surgery in patients with uncomplicated course and those developing SIRS or septic complications. CONCLUSIONS: In patients undergoing cardiac surgery the monitoring of pre- and immediate postoperative HLA-DR levels during the first 24 h does not help to predict increased risk for postoperative SIRS/sepsis or infectious complications.
Assuntos
Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Antígenos HLA-DR/sangue , Inflamação/diagnóstico , Sepse/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Inflamação/etiologia , Inflamação/imunologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Fatores de Risco , Sepse/etiologia , Sepse/imunologiaRESUMO
COP9 signalosome (CSN) cleaves the ubiquitin-like protein Nedd8 from the Cul1 subunit of SCF ubiquitin ligases. The Jab1/MPN domain metalloenzyme (JAMM) motif in the Jab1/Csn5 subunit was found to underlie CSN's Nedd8 isopeptidase activity. JAMM is found in proteins from archaea, bacteria, and eukaryotes, including the Rpn11 subunit of the 26S proteasome. Metal chelators and point mutations within JAMM abolished CSN-dependent cleavage of Nedd8 from Cul1, yet had little effect on CSN complex assembly. Optimal SCF activity in yeast and both viability and proper photoreceptor cell (R cell) development in Drosophila melanogaster required an intact Csn5 JAMM domain. We propose that JAMM isopeptidases play important roles in a variety of physiological pathways.
Assuntos
Proteínas de Ciclo Celular/metabolismo , Proteínas Culina , Proteínas de Ligação a DNA/química , Proteínas de Ligação a DNA/metabolismo , Metaloendopeptidases/química , Metaloendopeptidases/metabolismo , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo , Ubiquitinas/metabolismo , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Complexo do Signalossomo COP9 , Carbono-Nitrogênio Liases/metabolismo , Proteínas de Drosophila , Drosophila melanogaster/crescimento & desenvolvimento , Drosophila melanogaster/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Metaloendopeptidases/genética , Dados de Sequência Molecular , Mutação , Proteína NEDD8 , Peptídeo Hidrolases , Peptídeo Sintases/metabolismo , Proteínas Ligases SKP Culina F-Box , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/química , Proteínas de Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/metabolismo , Schizosaccharomyces/genética , Schizosaccharomyces/metabolismo , Alinhamento de Sequência , TemperaturaRESUMO
OBJECTIVE: To evaluate patients without prior pulmonary disease after cardiac surgery and to determine whether resistive unloading by automatic tube compensation, pressure support ventilation, and continuous positive airway pressure has different effects on oxygen consumption, breathing pattern, gas exchange, and hemodynamics. DESIGN: Prospective, randomized, controlled study. SETTING: Tertiary care, postoperative intensive care unit. PATIENTS: Twenty-one patients scheduled for open heart coronary artery bypass graft surgery. INTERVENTIONS: Each patient was ventilated with all three modes in random order. MEASUREMENTS AND MAIN RESULTS: Patients were ventilated in three modes, each applied for 30 mins according to computer-generated randomization: pressure support ventilation with 5 cm H2O, continuous positive airway pressure, and automatic tube compensation. Oxygen consumption was calculated by means of indirect calorimetry. The hypnotic state of the patients was monitored by Bispectral Index. For hemodynamic measurements, a fiberoptic pulmonary artery catheter was inserted. The main finding of our study was that oxygen consumption and breathing pattern (tidal volume and respiratory rate) did not differ significantly during automatic tube compensation and pressure support ventilation compared with continuous positive airway pressure (oxygen consumption, 170 +/- 29 vs. 170 +/- 26 vs. 174 +/- 29 mL.min.m, respectively; tidal volume, 466 +/- 132 vs. 484 +/- 125 vs. 470 +/- 119 mL, respectively; respiratory rate, 16 +/- 4 vs. 15 +/- 4 vs. 16 +/- 4 breaths/min, respectively). Automatic tube compensation and pressure support ventilation had no clinical effects on gas exchange and hemodynamic variables compared with continuous positive airway pressure. None of the variables differed significantly during the three ventilatory settings. CONCLUSION: In postoperative tracheally intubated patients with normal ventilatory demand, automatic tube compensation and pressure support ventilation with 5 cm H2O lead to identical oxygen consumption, breathing patterns, gas exchange, and hemodynamics. We, therefore, suggest that this group of patients does not need any additional positive pressure support from the ventilator to overcome the additional work of breathing imposed by the endotracheal tube during the weaning phase from mechanical ventilation.