RESUMO
Patients with HPV--localized head and neck cancer (HNC) show inferior outcomes after surgery and radiochemotherapy compared to HPV-associated cancers. The underlying mechanisms remain elusive, but differences in immune status and immune activity may be implicated. In this study, we analyzed immune profiles of CD8+ T cells and myeloid-derived suppressor cells (MDSC) in HPV+ versus HPV- disease.The overall frequency of CD8+ T cells was reduced in HNC versus healthy donors but substantially increased after curative therapy (surgery and/or radiochemotherapy). In HPV+ patients, this increase was associated with significant induction of peripheral blood CD8+/CD45RA-/CD62L- effector memory cells. The frequency of HPV-antigen-specific CD8+ cells was low even in patients with virally associated tumors and dropped to background levels after curative therapy. Pre-therapeutic counts of circulating monocytic MDSC, but not PMN-MDSC, were increased in patients with HPV- disease. This increase was accompanied by reduced fractions of terminally differentiated CD8+ effector cells. HPV- tumors showed reduced infiltrates of CD8+ and CD45RO+ immune cells compared with HPV+ tumors. Importantly, frequencies of tumor tissue-infiltrating PMN-MDSC were increased, while percentages of Granzyme B+ and Ki-67+ CD8 T cells were reduced in patients with HPV- disease.We report differences in frequencies and relative ratios of MDSC and effector T cells in HPV- HNC compared with more immunogenic HPV-associated disease. Our data provide new insight into the immunological profiles of these two tumor entities and may be utilized for more tailored immunotherapeutic approaches in the future.
Assuntos
Neoplasias de Cabeça e Pescoço , Células Supressoras Mieloides , Infecções por Papillomavirus , Humanos , Linfócitos T CD8-Positivos , Infecções por Papillomavirus/complicações , Neoplasias de Cabeça e Pescoço/patologia , Antígenos Comuns de LeucócitoAssuntos
Seios Paranasais , Sinusite , Humanos , Seio Esfenoidal , Seios Paranasais/cirurgia , Sinusite/cirurgia , EndoscopiaRESUMO
Mucous membrane pemphigoid (MMP) is a pemphigoid disease with predominant mucous membrane involvement. It mainly affects the mucous membranes of the mouth, eyes, nose and pharynx, but also the larynx, trachea, esophagus, genital and perianal regions. The manifestation of the disease covers a wide spectrum from gingival erythema and single oral lesions to severe tracheal strictures that obstruct breathing and conjunctival scarring with marked visual impairment and, not infrequently, blindness. In addition to a clinical picture of predominant mucosal involvement, diagnosis is based on direct immunofluorescence of a peri-lesional biopsy and serology. The main target antigen is BP180 (collagen XVII), and reactivity with laminin 332 is associated with malignancy in approximately 25 % of MMP patients. The treatment of MMP is challenging. On the one hand, due to the involvement of different mucous membranes, good interdisciplinary cooperation is required; on the other hand, due to the rarity of the disease, no randomized controlled clinical trials are available. The aim of this guideline is to present the clinical picture, including severity and scoring systems, and to give guidance for diagnosing and treating this complex disease. In MMP, interdisciplinary cooperation plays an essential role as well as the prompt diagnosis and initiation of adequate therapy in order to avoid irreversible damage to the mucous membranes with serious complications.
Assuntos
Penfigoide Mucomembranoso Benigno , Penfigoide Bolhoso , Humanos , Penfigoide Bolhoso/patologia , Penfigoide Mucomembranoso Benigno/diagnóstico , Penfigoide Mucomembranoso Benigno/terapia , Mucosa/patologia , Técnica Direta de Fluorescência para Anticorpo , BiópsiaRESUMO
PURPOSE: Transoral robotic surgery (TORS) has the potential to improve some inherent disadvantages of transoral laser microsurgery (TLM). Here, we retrospectively assessed the application of the Medrobotics Flex system for the resection of supraglottic carcinomas compared to TLM. METHODS: 84 patients underwent surgery for supraglottic carcinomas with the Flex robotic system (n = 19, T-stage distribution in %: T1 42, T2 47, T3 11, T4 0) or TLM (n = 65, T-stage distribution in %: T1 40, T2 44, T3 14, T4 2). Clinical and oncologic parameters were compared. RESULTS: All surgeries were successfully completed with the Flex system and tracheostomy rate was 13%. For patients with adequate follow-up, 24-month disease-free survival was 71.4% (n = 5/7) after TORS compared to 64.9% (n = 24/37) after TLM. Local recurrence rates were 0% for TORS and 11% for TLM. CONCLUSIONS: Initial results for supraglottic carcinoma resection using the Medrobotics Flex system are encouraging with excellent local tumor control.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Laríngeas , Terapia a Laser , Procedimentos Cirúrgicos Robóticos , Carcinoma de Células Escamosas/cirurgia , Humanos , Neoplasias Laríngeas/cirurgia , Lasers , Microcirurgia , Recidiva Local de Neoplasia/cirurgia , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Patients suffering from squamous cell carcinoma of the larynx (LSCC) with lymphatic metastasis have a relatively poor prognosis and often require radical therapeutic management. The mechanisms which drive metastasis to the lymph nodes are largely unknown but may be promoted by a pro-angiogenic tumor microenvironment. In this study, we examined whether the number of microvessels and the expression level of vascular endothelial growth factor (VEGF) in the primary tumor are correlated with the degree of lymph node metastasis (N-stage), tumor staging (T) and survival time in LSCC patients. METHODS: Tissue-Microarrays of 97 LSCC patients were analyzed using immunohistochemistry. The expression of VEGF was scored as intensity of staining (low vs high) and the number of CD31-positive vessels (median ≥7 vessels per visual field) was counted manually. Scores were correlated with N-stage, T-stage and 5-year overall survival rate. RESULTS: A high expression of angiogenic biomarkers was not associated with poor overall survival in the overall cohort of patients. Instead high CD31 count was associated with early stage cancer (p = 0.004) and in this subgroup high VEGF expression correlated with poor survival (p = 0.032). Additionally, in early stage cancer a high vessel count was associated with an increased recurrence rate (p = 0.004). CONCLUSION: Only in the early stage subgroup a high expression of angiogenic biomarkers was associated with reduced survival and an increased rate of recurrence. Thus, biomarkers of angiogenesis may be useful to identify high risk patients specifically in early stage LSCC.
Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/secundário , Neoplasias Laríngeas/patologia , Recidiva Local de Neoplasia/patologia , Molécula-1 de Adesão Celular Endotelial a Plaquetas/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismo , Carcinoma de Células Escamosas/metabolismo , Feminino , Seguimentos , Humanos , Neoplasias Laríngeas/metabolismo , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Recidiva Local de Neoplasia/metabolismo , Estadiamento de Neoplasias , Neovascularização Patológica , Taxa de SobrevidaRESUMO
BACKGROUND: The Flex Robotic System is a new robotic device specifically developed for transoral robotic surgery (TORS). METHODS: We performed a prospective clinical study, assessing the safety and efficacy of the Medrobotics Flex Robotic System. A total of 40 patients required a surgical procedure for benign lesions (n = 30) or T1 and T2 carcinomas (n = 10). Access and visualization of different anatomic subsites were individually graded by the surgeon. Setup times, access and visualization times, surgical results, as well as adverse events were documented intraoperatively. RESULTS: The lesions could be exposed and visualized properly in 38 patients (95%) who went on to have a surgical procedure performed with the Flex Robotic System, which were intraoperatively evaluated as successful. No serious adverse events occurred. CONCLUSION: Lesions in the oropharynx, hypopharynx, or supraglottic larynx could be successfully resected using the Flex Robotic System, thus making the system a safe and effective tool in transoral robotic surgery. © 2016 Wiley Periodicals, Inc. Head Neck 39: 471-475, 2017.
Assuntos
Neoplasias Hipofaríngeas/cirurgia , Cirurgia Endoscópica por Orifício Natural/métodos , Neoplasias Orofaríngeas/cirurgia , Procedimentos Cirúrgicos Robóticos/instrumentação , Robótica , Adulto , Idoso , Biópsia por Agulha , Desenho de Equipamento , Segurança de Equipamentos , Feminino , Humanos , Neoplasias Hipofaríngeas/patologia , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Cirurgia Endoscópica por Orifício Natural/instrumentação , Duração da Cirurgia , Neoplasias Orofaríngeas/patologia , Segurança do Paciente , Estudos Prospectivos , Procedimentos Cirúrgicos Robóticos/métodos , Resultado do TratamentoRESUMO
OBJECTIVES/HYPOTHESIS: To evaluate the application of the Flex Robotic System in transoral robotic surgery (TORS). STUDY DESIGN: Multicenter, prospective, open-label, single-armed clinical study. METHODS: A prospective clinical follow-up multicenter study was performed from July 2014 to October 2015 assessing the safety and efficacy of the Medrobotics Flex Robotic System for access and visualization of the oropharynx, hypopharynx, and larynx as well as for resection of benign and malignant lesions. A total of 80 patients were enrolled. Access and visualization of five anatomic subsites (base of tongue, palatine tonsil area, epiglottis, posterior pharyngeal wall, and false vocal cords) were individually graded by the surgeon. Setup times, access and visualization times, surgical results, and adverse events were documented. RESULTS: The relevant anatomic structures could be exposed and visualized properly in 75 patients, who went on to have a surgical procedure performed with the Flex Robotic System. Access and visualization of the palatine tonsil area, posterior pharyngeal wall, epiglottis, and posterior pharyngeal wall were excellent. However, false vocal cords and vocal cords were more difficult to expose. Seventy-two patients were treated successfully with the Flex Robotic System. There were no serious or unanticipated device-related adverse events caused by the Flex Robotic System. CONCLUSIONS: Lesions in the oropharynx, hypopharynx, and larynx could be successfully resected with the Flex Robotic System, specifically developed for TORS. Our study provides evidence that the Flex Robotic System is a safe and effective tool in TORS. Laryngoscope, 2016 127:391-395, 2017.
Assuntos
Neoplasias Hipofaríngeas/cirurgia , Doenças da Laringe/cirurgia , Neoplasias Laríngeas/cirurgia , Laringoscópios , Neoplasias Orofaríngeas/cirurgia , Procedimentos Cirúrgicos Robóticos/instrumentação , Idoso , Biópsia/instrumentação , Desenho de Equipamento , Falha de Equipamento , Feminino , Seguimentos , Humanos , Neoplasias Hipofaríngeas/patologia , Hipofaringe/patologia , Hipofaringe/cirurgia , Doenças da Laringe/patologia , Neoplasias Laríngeas/patologia , Laringe/patologia , Laringe/cirurgia , Curva de Aprendizado , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/patologia , Orofaringe/patologia , Orofaringe/cirurgia , Vigilância de Produtos Comercializados , Estudos Prospectivos , Procedimentos Cirúrgicos Robóticos/educaçãoRESUMO
Following genotoxic stress, cells activate a complex signalling network to arrest the cell cycle and initiate DNA repair or apoptosis. The tumour suppressor p53 lies at the heart of this DNA damage response. However, it remains incompletely understood, which signalling molecules dictate the choice between these different cellular outcomes. Here, we identify the transcriptional regulator apoptosis-antagonizing transcription factor (AATF)/Che-1 as a critical regulator of the cellular outcome of the p53 response. Upon genotoxic stress, AATF is phosphorylated by the checkpoint kinase MK2. Phosphorylation results in the release of AATF from cytoplasmic MRLC3 and subsequent nuclear translocation where AATF binds to the PUMA, BAX and BAK promoter regions to repress p53-driven expression of these pro-apoptotic genes. In xenograft experiments, mice exhibit a dramatically enhanced response of AATF-depleted tumours following genotoxic chemotherapy with adriamycin. The exogenous expression of a phospho-mimicking AATF point mutant results in marked adriamycin resistance in vivo. Nuclear AATF enrichment appears to be selected for in p53-proficient endometrial cancers. Furthermore, focal copy number gains at the AATF locus in neuroblastoma, which is known to be almost exclusively p53-proficient, correlate with an adverse prognosis and reduced overall survival. These data identify the p38/MK2/AATF signalling module as a critical repressor of p53-driven apoptosis and commend this pathway as a target for DNA damage-sensitizing therapeutic regimens.
Assuntos
Proteínas Reguladoras de Apoptose/fisiologia , Apoptose/fisiologia , Dano ao DNA/fisiologia , Proteínas Repressoras/fisiologia , Proteína Supressora de Tumor p53/fisiologia , Transporte Ativo do Núcleo Celular , Sequência de Aminoácidos , Animais , Proteínas Reguladoras de Apoptose/genética , Pontos de Checagem do Ciclo Celular , Dano ao DNA/genética , Doxorrubicina/farmacologia , Resistencia a Medicamentos Antineoplásicos/genética , Neoplasias do Endométrio/genética , Feminino , Amplificação de Genes , Dosagem de Genes , Células HEK293 , Humanos , Camundongos , Dados de Sequência Molecular , Complexos Multiproteicos , Cadeias Leves de Miosina/metabolismo , Neuroblastoma/genética , Neuroblastoma/mortalidade , Pressão Osmótica , Fosforilação , Prognóstico , Processamento de Proteína Pós-Traducional , Proteínas Repressoras/genéticaRESUMO
Following genotoxic stress, cells activate a complex kinase-based signaling network to arrest the cell cycle and initiate DNA repair. p53-defective tumor cells rewire their checkpoint response and become dependent on the p38/MK2 pathway for survival after DNA damage, despite a functional ATR-Chk1 pathway. We used functional genetics to dissect the contributions of Chk1 and MK2 to checkpoint control. We show that nuclear Chk1 activity is essential to establish a G(2)/M checkpoint, while cytoplasmic MK2 activity is critical for prolonged checkpoint maintenance through a process of posttranscriptional mRNA stabilization. Following DNA damage, the p38/MK2 complex relocalizes from nucleus to cytoplasm where MK2 phosphorylates hnRNPA0, to stabilize Gadd45α mRNA, while p38 phosphorylates and releases the translational inhibitor TIAR. In addition, MK2 phosphorylates PARN, blocking Gadd45α mRNA degradation. Gadd45α functions within a positive feedback loop, sustaining the MK2-dependent cytoplasmic sequestration of Cdc25B/C to block mitotic entry in the presence of unrepaired DNA damage. Our findings demonstrate a critical role for the MK2 pathway in the posttranscriptional regulation of gene expression as part of the DNA damage response in cancer cells.