RESUMO
OBJECTIVE: To evaluate the efficacy and safety of an oral selective tyrosine kinase 2 (TYK2) inhibitor, deucravacitinib, in patients with active psoriatic arthritis (PsA). METHODS: In this double-blind, phase II trial, 203 patients with PsA were randomised 1:1:1 to placebo, deucravacitinib 6 mg once a day or 12 mg once a day. The primary endpoint was American College of Rheumatology-20 (ACR-20) response at week 16. RESULTS: ACR-20 response was significantly higher with deucravacitinib 6 mg once a day (52.9%, p=0.0134) and 12 mg once a day (62.7%, p=0.0004) versus placebo (31.8%) at week 16. Both deucravacitinib doses resulted in significant improvements versus placebo (p≤0.05) in the multiplicity-controlled secondary endpoints of change from baseline in Health Assessment Questionnaire-Disability Index and Short Form-36 Physical Component Summary score and in Psoriasis Area and Severity Index-75 response. Improvements were also seen in multiple exploratory endpoints with deucravacitinib treatment. The most common adverse events (AEs) (≥5%) in deucravacitinib-treated patients were nasopharyngitis, upper respiratory tract infection, sinusitis, bronchitis, rash, headache and diarrhoea. There were no serious AEs and no occurrence of herpes zoster, opportunistic infections and major adverse cardiovascular events, or differences versus placebo in mean changes in laboratory parameters with deucravacitinib treatment. CONCLUSIONS: Treatment with the selective TYK2 inhibitor deucravacitinib was well tolerated and resulted in greater improvements than placebo in ACR-20, multiplicity-controlled secondary endpoints and other exploratory efficacy measures in patients with PsA. Larger trials over longer periods of time with deucravacitinib are warranted to confirm its safety profile and benefits in PsA. TRIAL REGISTRATION NUMBER: NCT03881059.
Assuntos
Antirreumáticos , Artrite Psoriásica , Antirreumáticos/uso terapêutico , Artrite Psoriásica/induzido quimicamente , Artrite Psoriásica/tratamento farmacológico , Método Duplo-Cego , Compostos Heterocíclicos , Humanos , Índice de Gravidade de Doença , TYK2 Quinase , Resultado do TratamentoAssuntos
Astrocitoma/diagnóstico por imagem , Neoplasias Encefálicas/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Cefaleia/etiologia , Astrocitoma/complicações , Neoplasias Encefálicas/complicações , Criança , Feminino , Cefaleia/diagnóstico por imagem , Humanos , Hidrocefalia/diagnóstico por imagem , Hidrocefalia/etiologia , Imageamento por Ressonância Magnética , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To evaluate the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to or intolerance of tumor necrosis factor (TNF) inhibitors. METHODS: In this phase III study, 551 patients were randomized (1:1:1:1) to receive intravenous secukinumab at a dose of 10 mg/kg (at baseline and weeks 2 and 4) followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks or, alternatively, abatacept or placebo on the same dosing schedule. The primary end point was the proportion of patients achieving 20% improvement in disease activity according to the American College of Rheumatology response criteria (ACR20) at week 24 in the secukinumab 150 mg or 75 mg treatment groups as compared with placebo. Key secondary end points included change from baseline to week 24 in the Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) and the Health Assessment Questionnaire disability index (HAQ DI), as well as the ACR 50% improvement (ACR50) response rate at week 24. RESULTS: The primary efficacy end point was met in patients receiving 150 mg secukinumab, in whom the ACR20 response rate at week 24 was significantly higher than that in the placebo group. The ACR20 response rates at week 24 were 30.7% in patients receiving 150 mg secukinumab (P = 0.0305), 28.3% in those receiving 75 mg secukinumab (P = 0.0916), and 42.8% in those receiving abatacept, compared with 18.1% in the placebo group. A significant reduction in the DAS28-CRP was seen in patients treated with 150 mg secukinumab (P = 0.0495), but not in patients treated with 75 mg secukinumab. Improvements in the HAQ DI and ACR50 response rates were not significant in the 2 secukinumab dose groups compared with the placebo group. The overall safety profile was similar across all treatment groups. CONCLUSION: Secukinumab at a dose of 150 mg resulted in improvement in signs and symptoms and reduced disease activity in patients with active RA who had an inadequate response to TNF inhibitors. Improvements observed with abatacept were numerically higher than with secukinumab. There were no new or unexpected safety signals with secukinumab in this study.
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Anticorpos Monoclonais/administração & dosagem , Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Administração Intravenosa , Adulto , Anticorpos Monoclonais Humanizados , Artrite Reumatoide/sangue , Proteína C-Reativa/análise , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Tumour necrosis factor alpha (TNFalpha) inhibitors are frequently used to treat rheumatoid arthritis, but whether use of a different TNFalpha inhibitor can improve patient response is unknown. We assess the efficacy and safety of the TNFalpha inhibitor golimumab in patients with active rheumatoid arthritis who had previously received one or more TNFalpha inhibitors. METHODS: 461 patients with active rheumatoid arthritis from 82 sites in 10 countries were randomly allocated by interactive voice response system, stratified by study site and methotrexate use, to receive subcutaneous injections of placebo (n=155), 50 mg golimumab (n=153), or 100 mg golimumab (n=153) every 4 weeks between Feb 21, 2006, and Sept 26, 2007. Allocation was double-blind. Eligible patients had been treated with at least one dose of a TNFalpha inhibitor previously. Patients continued stable doses of methotrexate, sulfasalazine, hydroxychloroquine, oral corticosteroids, and non-steroidal anti-inflammatory drugs. The primary endpoint was achievement at week 14 of 20% or higher improvement in American College of Rheumatology criteria for assessment of rheumatoid arthritis (ACR20). At week 16, patients who had less than 20% improvement in tender and swollen joint counts were given rescue therapy and changed treatment from placebo to 50 mg golimumab, or from 50 mg to 100 mg golimumab. Drug efficacy was assessed by intention to treat and safety was assessed according to the study drug given. This study is registered with ClinicalTrials.gov, number NCT00299546. FINDINGS: Patients had discontinued previous TNFalpha inhibitors because of lack of effectiveness (269 [58%] patients) or reasons unrelated to effectiveness (246 [53%] patients), such as intolerance and accessibility issues. Patients had active disease, which was indicated by a median of 14.0 (IQR 9.0-22.0) swollen and 26.0 (16.0-41.0) tender joints for the whole group. 28 (18%) patients on placebo, 54 (35%) patients on 50 mg golimumab (odds ratio 2.5 [95% CI 1.5-4.2], p=0.0006), and 58 (38%) patients on 100 mg golimumab (2.8 [1.6-4.7], p=0.0001) achieved ACR20 at week 14. Two patients were never treated, and 57 patients did not complete the study because of adverse events, unsatisfactory treatment effect, loss to follow-up, death, or other reasons. 155 patients on placebo, 153 on 50 mg golimumab, and 153 on 100 mg golimumab were assessed for drug efficacy. For weeks 1-16, serious adverse events were recorded in 11 (7%) patients on placebo, 8 (5%) on 50 mg golimumab, and 4 (3%) on 100 mg golimumab. For weeks 1-24, after some patients were given rescue therapy, serious adverse events were recorded in 15 (10%) patients on placebo, 14 (5%) on 50 mg golimumab, and 8 (4%) on 100 mg golimumab. INTERPRETATION: Golimumab reduced the signs and symptoms of rheumatoid arthritis in patients with active disease who had previously received one or more TNFalpha inhibitors. FUNDING: Centocor Research and Development and Schering-Plough Research Institute.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adalimumab , Análise de Variância , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais Humanizados , Antirreumáticos/efeitos adversos , Artrite Reumatoide/diagnóstico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Etanercepte , Feminino , Seguimentos , Humanos , Imunoglobulina G/uso terapêutico , Infliximab , Injeções Subcutâneas , Masculino , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Receptores do Fator de Necrose Tumoral/uso terapêutico , Indução de Remissão , Segurança , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND: Endoscopic repair of skull base (SB) defects is successful in over 90% of cases. Certain factors may contribute to failure of SB repair techniques or need for secondary repair. METHODS: Five-year retrospective review of endoscopic SB defect repairs performed by a single surgeon. RESULTS: Eighty-nine patients undergoing 110 procedures to repair 97 SB defects were evaluated. Etiology of defects included surgical/iatrogenic (64%), spontaneous (17%), traumatic (12%), congenital (6%), and idiopathic (1%). Defects occurred in the sella (41%), sphenoid sinus (18%), ethmoid roof (17%), olfactory cleft (16%), frontal sinus/recess (6%), and middle cranial fossa (2%). Sixty-three patients (71%) underwent primary SB defect repair and 26 patients underwent secondary repair (29%). In revision cases, mean number of prior repair attempts was 1.5 (range, 1-4). Factors potentially contributing to need for secondary SB defect repair included inability to localize SB defect (p =0 .008), development of new SB defect, prior sinus or SB surgery (p < 0.001), prior craniotomy (p < 0.001), prior radiation therapy (p = 0.002), and intracranial infection (p = 0.023). SB defects were successfully closed in 83 patients overall (93%), with success achieved in 97% of primary patients and 85% of secondary patients. Of failures, 3 patients required craniotomy for defect closure, 2 patients underwent permanent cerebrospinal fluid (CSF) diversion, and 1 patient has persistent CSF rhinorrhea. CONCLUSION: Although endoscopic repair of SB defect remains largely successful, certain factors should alert the surgeon to the potential for failure of repair or need for secondary SB defect repair.
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Rinorreia de Líquido Cefalorraquidiano/cirurgia , Encefalocele/cirurgia , Endoscopia , Base do Crânio/cirurgia , Adolescente , Adulto , Idoso , Rinorreia de Líquido Cefalorraquidiano/etiologia , Criança , Pré-Escolar , Craniotomia , Erros de Diagnóstico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radioterapia , Estudos Retrospectivos , Base do Crânio/efeitos da radiação , Neoplasias Cranianas/complicações , Falha de TratamentoRESUMO
OBJECTIVE: To describe the endoscopic management of frontal sinus mucoeceles with anterior table erosion. Previous hardware exposure and subsequent contour defects were also assessed. DESIGN: Retrospective case series. METHODS: Thirty-seven patients (mean 48 yrs, range 20-78) with frontal sinus mucoeceles and anterior table erosion, endoscopically managed in a tertiary care setting, were reviewed. The demographic data, defect size, surgical technique, presence of exposed hardware, outcomes, and clinical follow-up were collected for outcome assessment RESULTS: The average follow-up was 32.6 months (range, 6-73). The overall long-term success rate with our initial endoscopic approach was 92% (34/37). The average size of anterior table defects was 181 mm2 (4-1155). Twelve patients had prior osteoplastic flaps (OPF) with obliteration and 57% (21/37) had previous endoscopic sinus surgeries. Ten patients with prior OPF operations had hardware exposed within the sinus from previous surgeries. Two patients eventually required an OPF with fat obliteration. Most defects were either unnoticeable or cosmetically acceptable to the patients. Only one patient required a contouring plate six months after the procedure. Ninety percent of patients were successfully managed with exposed hardware left in situ. CONCLUSIONS: Endoscopic marsupialization of frontal sinus mucoeceles with anterior table erosion has a high success rate with a good cosmetic outcome, often without routine reconstruction. Revision cases and those with exposed hardware did not prevent successful management.
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Endoscopia , Seio Frontal/cirurgia , Mucocele/cirurgia , Adulto , Idoso , Feminino , Seguimentos , Seio Frontal/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Mucocele/diagnóstico por imagem , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do TratamentoRESUMO
BACKGROUND: Surfactant-associated proteins (SP) A and D are both innate immunity mediators and produced in normal and diseased sinus mucosa. Cystic fibrosis (CF) is associated with Th1 adaptive inflammation whereas allergic fungal rhinosinusitis (AFRS) is associated with Th2 adaptive inflammation. The purpose of this study is to show and quantify the presence of SP A, SP D, tumor necrosis factor (TNF) alpha, (a Th1 marker), and eotaxin (a Th2 marker) in normal and diseased sinus mucosa. METHODS: Intraoperative sinus mucosal biopsy specimens from human volunteers were obtained during endoscopic sinus surgery for CF (n = 4), AFRS (n = 10), and normal controls (CTLs; n = 4). Specimens were evaluated for presence and quantity of SP A, SP D, and TNF-alpha using Western blot with semiquantitative immunoblot analysis. Eotaxin was quantified using ELISA immunoassay. Results were standardized and reported as picograms of mediator per microgram of total protein. RESULTS: SP A, SP D, and TNF-alpha levels in CF tissue extracts were 2-10 times higher than levels in AFRS tissue (with SP D and TNF-alpha reaching statistical significance) but CF tissue was not significantly higher than CTL tissue. SP A, SP D, and TNF-alpha were not significantly elevated in AFRS. Eotaxin showed elevated levels in CF and AFRS when compared with CTLs (p = 0.03 and 0.003, respectively). CONCLUSION: SP D and TNF-alpha are significantly increased in CF compared with AFRS, suggesting activation of both innate immunity and Th1-mediated inflammation and potential correlation between SPs and downstream adaptive immune responses.
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Fibrose Cística/imunologia , Fibrose Cística/patologia , Proteínas Fúngicas/química , Regulação da Expressão Gênica , Imunidade Inata , Mucosa Respiratória/microbiologia , Rinite Alérgica Perene/imunologia , Rinite Alérgica Perene/microbiologia , Quimiocina CCL11/metabolismo , Fibrose Cística/metabolismo , Humanos , Sistema Imunitário , Inflamação , Modelos Biológicos , Mucosa , Proteína A Associada a Surfactante Pulmonar/metabolismo , Proteína D Associada a Surfactante Pulmonar/metabolismo , Células Th1 , Fator de Necrose Tumoral alfa/metabolismoRESUMO
BACKGROUND: The aim of this study was to compare three different techniques for transsphenoidal pituitary surgery: (1) sublabial transseptal approach with microscopic resection, (2) transnasal transseptal approach with endoscopic resection, and (3) endoscopic approach with endoscopic resection. METHODS: We performed a retrospective review of 50 pituitary surgeries performed by the same neurosurgeon. Demographic, radiographic, and clinical data were collected. RESULTS: Fifteen patients underwent sublabial approach with microscopic tumor resection, 21 patients underwent the transnasal approach with endoscopic resection, and 14 patients underwent the completely endoscopic technique. There were a total of 20 complications in the sublabial group, 13 transnasal complications, and 6 endoscopic complications. Cerebrospinal fluid leak incidence was 53% in the sublabial approaches, 47% transnasal, and 28% in the endoscopic patients. Diabetes insipidus was encountered in 33% of sublabial approaches, 5% of transnasal approaches, and 7% of endoscopic approaches. Lumbar drains were required in 40% of sublabial approaches, 38% of transnasal approaches, and 7% of endoscopic approaches. Nasal packing was used in 100% of sublabial and transnasal approaches and 0% of endoscopic approaches. Mean recurrence rate and follow-up was sublabial in 6.6% (50 months), transnasal in 9.5% (11 months), and endoscopic in 0% (7 months). Average hospital stay for sublabial approaches, transnasal approaches, and endoscopic approaches was 8.3, 6.2, and 3.4 days, respectively (p < 0.05). CONCLUSION: Transsphenoidal pituitary surgery has evolved over the past several decades, because advances in technology have been the catalyst for minimally invasive surgeries. Less invasive approaches, such as the transnasal approach with endoscopic resection of tumor and the completely endoscopic .technique have less morbidity and a shorter hospital stay than traditional sublabial approaches. Continued follow-up is needed to confirm long-term benefits and similar recurrence rates.
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Endoscopia/métodos , Procedimentos Cirúrgicos Otorrinolaringológicos/métodos , Neoplasias Hipofisárias/cirurgia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Estudos RetrospectivosRESUMO
INTRODUCTION: Surfactant-associated proteins (SPs) play a crucial role in the innate defense system and serve as the initial step in the immune response to inhaled pathogens. SP-A and SP-D expression and function are altered in a variety of inflammatory and infectious diseases of the lungs, such as asthma, allergies, and cystic fibrosis, but their presence and function in the sinonasal cavity has not been investigated. The objective of this study was to test our hypothesis that SP-A and SP-D are present in the human sinus. MATERIALS AND METHODS: Sinus mucosal biopsies were performed in 8 patients undergoing endoscopic sinus surgery for chronic rhinosinusitis with nasal polyposis, pituitary tumors, and cerebrospinal fluid leak repairs. Expression of SP mRNA and protein by the sinus mucosa was detected by RT-PCR and immunoblot analysis, respectively. RESULTS: Analyses of mucosal biopsies from these patients revealed the presence of SP-A and SP-D mRNA and protein in all specimens. CONCLUSION: SP-A and SP-D are expressed in both normal and diseased human sinus tissue. Understanding the role of SPs in diseased and healthy states may elucidate their possible roles in innate immunity in the upper airway and allow us to develop novel treatments for sinonasal pathologies.
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Seios Paranasais , Proteína A Associada a Surfactante Pulmonar/análise , Proteína D Associada a Surfactante Pulmonar/análise , Mucosa Respiratória/química , Western Blotting , Humanos , Proteína A Associada a Surfactante Pulmonar/genética , Proteína D Associada a Surfactante Pulmonar/genética , RNA Mensageiro/análise , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Rejuvenation of the aging eyelid subunit provides a youthful appearance to one of the focal points of the face. As the age of our population increases, these procedures are likely to become increasingly more common. Accurate preoperative examination, assessment, and counseling are imperative to achieve an excellent result. As well, careful selection from the spectrum of available techniques, combined with meticulous surgical precision, will assist the surgeon in rejuvenating the individual patient. Although no one ideal surgical procedure exists, many safe and effective strategies have been developed as we have learned more about the effects of aging. This article aims to provide a history of techniques used in eyelid rejuvenation, as well as an overview of the evaluation process.
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Blefaroplastia , Pálpebras/patologia , Rejuvenescimento , Envelhecimento da Pele/patologia , Tecido Adiposo/cirurgia , Blefaroplastia/classificação , Blefaroplastia/métodos , Aconselhamento , Humanos , Planejamento de Assistência ao PacienteRESUMO
Highly migratory neuroectodermal cells share a common embryonic origin with cells of the central nervous system (CNS). They include enteric, parasympathetic, sympathoadrenal, and sensory neurons of the peripheral nervous system, Schwann cells, melanocytes, endocrine cells, and cells forming connective tissue of the face and neck. Because of their common embryologic origin, these cells and the tumors that derive from them can share genetic and antigenic phenotypes with gliomas, tumors derived from CNS glia. We recently discovered that chlorotoxin (ClTx), a 4-kD peptide purified from Leiurus quinquestriatus scorpion, is a highly specific marker for glioma cells in biopsy tissues (Soroceanu et al. Cancer Res 58:4871-4879, 1998) that can target tumors in animal models. We report on the specificity of ClTx as a marker for tumors of neuroectodermal origin that include peripheral neuroectodermal tumors (PNET) and gliomas. Specifically, we histochemically stained frozen and paraffin tissue sections of human biopsy tissues from 262 patients with a synthetically manufactured and biologically active ClTx bearing an N-terminal biotin. The vast majority (74 of 79) of primary human brain tumors investigated showed abundant binding of ClTx with greater than 90% ClTx-positive cells in each section. By comparison, 32 biopsies of uninvolved brain used for comparison were largely ClTx-negative, with only a few isolated reactive astrocytes showing some ClTx binding. However, as with gliomas, the vast majority of PNETs examined showed specific ClTx binding (31 of 34). These include medulloblastomas (4 of 4), neuroblastomas (6 of 7), ganglioneuromas (4 of 4), melanomas (7 of 7), adrenal pheochromocytomas (5 of 6), primitive PNET (1), small cell lung carcinoma (2 of 3), and Ewing's sarcoma (2 of 2). Under identical staining conditions, normal tissues from brain, skin, kidney, and lung were consistently negative for ClTx. These results suggest that chlorotoxin is a reliable and specific histopathological marker for tumors of neuroectodermal origin and that chlorotoxin derivatives with cytolytic activity may have therapeutic potential for these cancers.