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1.
Nature ; 605(7911): 741-746, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35508656

RESUMO

Phosphoinositide 3-kinase δ (PI3Kδ) has a key role in lymphocytes, and inhibitors that target this PI3K have been approved for treatment of B cell malignancies1-3. Although studies in mouse models of solid tumours have demonstrated that PI3Kδ inhibitors (PI3Kδi) can induce anti-tumour immunity4,5, its effect on solid tumours in humans remains unclear. Here we assessed the effects of the PI3Kδi AMG319 in human patients with head and neck cancer in a neoadjuvant, double-blind, placebo-controlled randomized phase II trial (EudraCT no. 2014-004388-20). PI3Kδ inhibition decreased the number of tumour-infiltrating regulatory T (Treg) cells and enhanced the cytotoxic potential of tumour-infiltrating T cells. At the tested doses of AMG319, immune-related adverse events (irAEs) required treatment to be discontinued in 12 out of 21 of patients treated with AMG319, suggestive of systemic effects on Treg cells. Accordingly, in mouse models, PI3Kδi decreased the number of Treg cells systemically and caused colitis. Single-cell RNA-sequencing analysis revealed a PI3Kδi-driven loss of tissue-resident colonic ST2 Treg cells, accompanied by expansion of pathogenic T helper 17 (TH17) and type 17 CD8+ T (TC17) cells, which probably contributed to toxicity; this points towards a specific mode of action for the emergence of irAEs. A modified treatment regimen with intermittent dosing of PI3Kδi in mouse models led to a significant decrease in tumour growth without inducing pathogenic T cells in colonic tissue, indicating that alternative dosing regimens might limit toxicity.


Assuntos
Antineoplásicos , Neoplasias de Cabeça e Pescoço , Adenosina/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Modelos Animais de Doenças , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Imunoterapia , Camundongos , Fosfatidilinositol 3-Quinases , Quinolinas/uso terapêutico , Linfócitos T Reguladores
2.
Oral Maxillofac Surg Clin North Am ; 26(2): 247-52, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24794269

RESUMO

Managing osteoradionecrosis (ORN) of the facial bones is a challenge in maxillofacial head and neck surgery. Changes in understanding of ORN of the jaws has led to new studies using novel therapeutic modalities to manage this disorder. These treatment regimens may allow medical management to replace major reconstructive surgery for some patients who have already undergone chemoradiotherapy or combined modality therapy for head and neck cancer.


Assuntos
Doenças Maxilomandibulares/tratamento farmacológico , Osteorradionecrose/tratamento farmacológico , Antibacterianos/uso terapêutico , Antioxidantes/uso terapêutico , Conservadores da Densidade Óssea/uso terapêutico , Quimiorradioterapia , Ácido Clodrônico/uso terapêutico , Terapia Combinada , Humanos , Oxigenoterapia Hiperbárica , Procedimentos Cirúrgicos Ortognáticos , Pentoxifilina/uso terapêutico , Protetores contra Radiação/uso terapêutico , Procedimentos de Cirurgia Plástica , Tocoferóis/uso terapêutico
3.
J Craniomaxillofac Surg ; 31(2): 88-91, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12628597

RESUMO

INTRODUCTION: Craniomaxillofacial surgeons require to estimate the orbital volume in a variety of clinical situations. This paper evaluates a new method based on software analysis of computerized tomography (CT) scan data. MATERIAL AND METHODS: Five dried skulls with prosthetic globes and periorbita were non-helically scanned in an Elscint 2400 CT scanner. Images obtained were processed using the "Analyze" software package and results compared to the volume of the intraorbital prosthesis as determined by a volume displacement gravimetric method. RESULTS: Estimates of volume produced by the software varied from the gold standard by 0.06-50.44%, with a mean error of 8.8%. CONCLUSION: Despite the use of a variety of scan protocols it was not possible to obtain results with "Analyze" software which were sufficiently accurate for clinical use.


Assuntos
Órbita/anatomia & histologia , Validação de Programas de Computador , Software , Tomografia Computadorizada por Raios X , Olho Artificial , Humanos , Órbita/diagnóstico por imagem , Desenho de Prótese , Reprodutibilidade dos Testes , Crânio/diagnóstico por imagem , Software/normas , Software/estatística & dados numéricos , Propriedades de Superfície , Cirurgia Assistida por Computador
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