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1.
Int J Cancer ; 146(6): 1717-1729, 2020 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-31709529

RESUMO

Cancers of the oral cavity remain the sixth most diagnosed cancer worldwide, with high rates of recurrence and mortality. We determined the role of STAT1 during oral carcinogenesis using two orthotopic models in mice genetically deficient for Stat1. Metastatic (LY2) and nonmetastatic (B4B8) head and neck squamous cell carcinoma (HNSCC) cell lines were injected into the oral cavity of Stat1 deficient (Stat1-/- ) and Stat1 competent (Stat1+/+ ) mice. Stat1-/- mice displayed increased tumor growth and metastasis compared to Stat1+/+ mice. Mechanistically, Stat1-/- mice displayed impaired CD4+ and CD8+ T-cell expansion compared to Stat1+/+ mice. This was associated with enhanced T-cell exhaustion, and severely attenuated T-cell antitumor effector responses including reduced expression of IFN-γ and perforin at the tumor site. Interestingly, tumor necrosis factor (TNF)-α production by T cells in tumor-bearing mice was suppressed by Stat1 deficiency. This deficiency in T-cell expansion and functional responses in mice was linked to PD-1 and CD69 overexpression in T cells of Stat1-/- mice. In contrast, we observed increased accumulation of CD11b+ Ly6G+ myeloid derived suppressor cells in tumors, draining lymph nodes, spleens and bone marrow of tumor-bearing Stat1-/- mice, resulting in a protumorigenic microenvironment. Our data demonstrates that STAT1 is an essential mediator of the antitumor response through inhibition of myeloid derived suppressor cell accumulation and promotion of T-cell mediated immune responses in murine head and neck squamous cell carcinoma. Selective induction of STAT1 phosphorylation in HNSCC patients could potentially improve oral tumor outcomes and response to therapy.


Assuntos
Imunomodulação , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/metabolismo , Fator de Transcrição STAT1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Linfonodos/patologia , Masculino , Camundongos , Camundongos Knockout , Metástase Neoplásica , Estadiamento de Neoplasias , Fator de Transcrição STAT1/deficiência , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral
2.
Oncology ; 98(1): 42-47, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31437849

RESUMO

INTRODUCTION: Smoking induces inflammation and an immune response. A cancer-related inflammatory response has been seen in smoking and nonsmoking head and neck squamous cell carcinoma (HNSCC) patients. OBJECTIVES: The aim of this study was to analyze the possible separated effects of smoking or HNSCC on 18 inflammatory or immune regulatory biomarkers. METHODS: Fifty-one nonsmoking and 36 smoking pretreated HNSCC patients and 101 nonsmoking and 39 smoking controls were included in this study. The levels of 18 inflammatory or immune regulatory biomarkers were analyzed. A multivariable linear regression model was used to predict the impact of smoking and HNSCC on the levels of the biomarkers. RESULTS: Smoking had the highest impact on total WBC, IFN-γ, and MCP-1 levels. The highest impact of HNSCC was found on neutrophils, neutrophil-to-lymphocyte ratio, HsCRP, MIP-1b, and TNF-α levels. CONCLUSION: IdentifyingHNSCC or smoking-related inflammatory biomarkers might contribute to the understanding of the immune response in HNSCC patients. This study could provide information of inflammatory biomarkers in HNSCC patients.


Assuntos
Biomarcadores/sangue , Fumar Cigarros , Mediadores da Inflamação/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Fumar Cigarros/efeitos adversos , Citocinas/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carga Tumoral , Adulto Jovem
3.
BMC Cancer ; 19(1): 830, 2019 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-31443700

RESUMO

BACKGROUND: The concept of head and neck cancers (HNSCC) having unique molecular signatures is well accepted but relating this to clinical presentation and disease behaviour is essential for patient benefit. Currently the clinical significance of HNSCC molecular subtypes is uncertain therefore personalisation of HNSCC treatment is not yet possible. METHODS: We performed meta-analysis on 8 microarray studies and identified six significantly up- (PLAU, FN1, CDCA5) and down-regulated (CRNN, CLEC3B and DUOX1) genes which were subsequently quantified by RT-qPCR in 100 HNSCC patient margin and core tumour samples. RESULTS: Retrospective correlation with sociodemographic and clinicopathological patient details identified two subgroups of opposing molecular signature (+q6 and -q6) that correlated to two recognised high-risk HNSCC populations in the UK. The +q6 group were older, male, and excessive alcohol users whilst the -q6 group were younger, female, paan-chewers and predominantly Bangladeshi. Additionally, all patients with tumour recurrence were in the latter subgroup. CONCLUSIONS: We provide the first evidence linking distinct molecular signatures in HNSCC with clinical presentations. Prospective trials are required to determine the correlation between these distinct genotypes and disease progression or treatment response. This is an important step towards the ultimate goal of improving outcomes by utilising personalised molecular-signature-guided treatments for HNSCC patients.


Assuntos
Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Biomarcadores Tumorais , Biologia Computacional/métodos , Mineração de Dados , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Masculino , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Seleção Genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Transcriptoma
4.
J Otolaryngol Head Neck Surg ; 48(1): 33, 2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31337433

RESUMO

BACKGROUND: Active tobacco smoking is a well-known risk factor for head and neck malignancy, and strong evidence has associated tobacco as the main carcinogenic factor in squamous cell cancers of this region. Evidence supporting a carcinogenic effect of second-hand smoke (SHS) on head and neck organs in non-smokers was also demonstrated with results consistent with those for active smokers. There is little data on the effects of SHS in patients previously treated for squamous cell carcinomas of the head and neck. OBJECTIVE: The purpose of this study was to prospectively evaluate the role of SHS on recurrence and survival in treated head and neck cancer patients. METHODS: We conducted a prospective cohort study to examine the association between self-reported SHS exposure and the risk of recurrence and mortality in patients treated for squamous cell cancers of the head and neck in a longitudinal fashion. Patients filled out an exhaustive smoking questionnaire on presentation and abbreviated questionnaires at each follow-up visit, which occurred every 6 months. Primary outcome measures were recurrence, development of a second primary malignancy, and recurrence-free survival. Chi square analysis was used to assess the association between SHS and the primary outcomes. A multivariate binary logistic regression analysis was applied to determine the independent predictors of recurrence. Cox proportional hazards and Kaplan Meier modeling were employed to assess the possible relationships between SHS exposure and time to develop the primary outcomes. RESULTS: Untreated new patients with a histologically confirmed diagnosis of first primary SCC of the UADT (defined as cancer of the oral cavity, the oropharynx, the hypopharynx, and the larynx) were recruited. Patients seen at The University of Texas Medical Branch (UTMB) Head and Neck oncology clinic from 1988 to 1996 were considered as cases in this study. One hundred and thirty-five patients were enrolled in the study. The median follow-up time for the sample was 54 months (3.92 years). Complete records were achieved for 92% of patients, thus 124 patients were included in the final analysis. SHS significantly correlated with recurrence and recurrence-free survival. The rate of recurrence was 46% in the group exposed to SHS and 22% in the non-exposed group. Based on multivariate binary logistic regression analysis, SHS exposure was detected as a significant independent predictor for recurrence (HR = 3.00 [95% CI 1.18-7.63]). Kaplan-Meier analysis demonstrated that patients who were not exposed to SHS had a statistically significant longer recurrence-free survival (log-rank P = 0.029). The mean survival for non SHS-exposed patients was 76 [63-89] months versus 54 [45-63] months for those exposed to SHS. CONCLUSIONS: SHS exposure is an independent predictor of recurrence and survival after head and neck cancer treatment. These results support the importance and efforts of reducing smoking at home in in the work-place.


Assuntos
Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Poluição por Fumaça de Tabaco/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Segunda Neoplasia Primária/etiologia , Estudos Prospectivos , Fatores de Risco , Taxa de Sobrevida
5.
Int J Mol Sci ; 20(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151143

RESUMO

Head and neck squamous cell carcinomas (HNSCC) encompass a heterogeneous group of solid tumors that arise from the upper aerodigestive tract. The tumor cells face multiple challenges including an acute demand of protein synthesis often driven by oncogene activation, limited nutrient and oxygen supply and exposure to chemo/radiotherapy, which forces them to develop adaptive mechanisms such as the Unfolded Protein Response (UPR). It is now well documented that the UPR, a homeostatic mechanism, is induced at different stages of cancer progression in response to intrinsic (oncogenic activation) or extrinsic (microenvironment) perturbations. This review will discuss the role of the UPR in HNSCC as well as in the key processes that characterize the physiology of HNSCC. The role of the UPR in the clinical context of HNSCC will also be addressed.


Assuntos
Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Resposta a Proteínas não Dobradas , Animais , Biomarcadores , Transformação Celular Neoplásica/metabolismo , Terapia Combinada , Humanos , Terapia de Alvo Molecular , Prognóstico , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Resultado do Tratamento , Resposta a Proteínas não Dobradas/efeitos dos fármacos , Resposta a Proteínas não Dobradas/efeitos da radiação
6.
Int J Mol Sci ; 20(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151182

RESUMO

Head and neck cancer encompass different malignancies that develop in and around the throat, larynx, nose, sinuses and mouth. Most head and neck cancers are squamous cell carcinomas (HNSCC) that arise in the flat squamous cells that makeup the thin layer of tissue on the surface of anatomical structures in the head and neck. Each year, HNSCC is diagnosed in more than 600,000 people worldwide, with about 50,000 new cases. HNSCC is considered extremely curable if detected early. But the problem remains in treatment of inoperable cases, residues or late stages. Circadian rhythm regulation has a big role in developing various carcinomas, and head and neck tumors are no exception. A number of studies have reported that alteration in clock gene expression is associated with several cancers, including HNSCC. Analyses on circadian clock genes and their association with HNSCC have shown that expression of PER1, PER2, PER3, CRY1, CRY2, CKIε, TIM, and BMAL1 are deregulated in HNSCC tissues. This review paper comprehensively presents data on deregulation of circadian genes in HNSCC and critically evaluates their potential diagnostics and prognostics role in this type of pathology.


Assuntos
Relógios Circadianos/genética , Ritmo Circadiano , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Animais , Relógios Biológicos/genética , Biomarcadores , Suscetibilidade a Doenças , Regulação Neoplásica da Expressão Gênica , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
7.
Artigo em Inglês | MEDLINE | ID: mdl-31133518

RESUMO

OBJECTIVE: This study sought to investigate the role of human papillomavirus (HPV) in the carcinogenesis of oral leukoplakia (OLK), with the oral cavity as the site of interest. STUDY DESIGN: A total of 76 patients (152 specimens) were enrolled in the study. The patients were divided into 2 groups: the malignant transformation of OLK (OLK-MT) group and the non-malignant transformation of OLK (OLK-non-MT) group. HPV reverse dot blot analysis, HPV DNA polymerase chain reaction (PCR), and p16INK4A immunohistochemistry (IHC) were used to determine HPV infection status. RESULTS: Transformation of OLK commonly occurred in the lateral/ventral tongue, buccal mucosa, and gingiva. On the basis of the initial analysis of specimens, only 5.3% (4 of 76) of patients were found to be HPV-16 positive, and these patients' final specimens yielded negative results. Overexpression of p16INK4A in the dysplastic stage was associated with the transformation of OLK (P = .013; odds ratio = 3.544). CONCLUSIONS: Transformation of OLK was common in patients who are elderly, in females, and in nonsmokers/nondrinkers; lesions were located in the lateral/ventral tongue, with dysplasia and overexpressed p16INK4A seen during the initial stage. HPV may be an opportunistic infection in the oral cavity and may not be a cause of malignant transformation of OLK. p16INK4A expression, which initially increases and then diminishes or disappears, may be an early predictor of malignant transformation.


Assuntos
Neoplasias de Cabeça e Pescoço , Leucoplasia Oral , Neoplasias Bucais/etiologia , Papillomaviridae , Infecções por Papillomavirus , Carcinoma de Células Escamosas de Cabeça e Pescoço , Idoso , Transformação Celular Neoplásica , Feminino , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Leucoplasia Oral/complicações , Infecções por Papillomavirus/complicações , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia
8.
Biomarkers ; 24(6): 574-583, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31002268

RESUMO

Purpose: To develop peripheral blood mRNA expression profiles of drug metabolizing enzymes (DMEs) as a surrogate to monitor tobacco induced head and neck squamous cell carcinoma (HNSCC), attempts were made to investigate (i) similarities in alterations with the cancer marker genes in biopsy samples and (ii) if alterations similar to that seen in biopsy samples are reflected in peripheral blood. Methods: Total RNA from eight soft gingival tissues and eight biopsy samples of HNSCC patients and total DNA and RNA from blood of healthy controls (n = 150) and HNSCC patients (n = 150) was processed for expression and genotyping studies. Blood from patients receiving chemo-radiotherapy was processed for follow-up study. Results: qRT-PCR revealed significant increase in mRNA expression of DMEs in biopsy and blood samples of HNSCC patients when compared to controls. Similar alterations were observed in cancer marker genes in these samples. Patients with variant genotypes of DMEs showed greater magnitude of alterations in mRNA expression when compared to wild type controls. Responders of chemo-radiotherapy showed significant decline in induction of mRNA expression of DMEs and cancer marker genes Conclusions: The data suggest that peripheral blood expression profiles could be used to monitor tobacco-induced HNSCC as well as the treatment response.


Assuntos
Biomarcadores Tumorais/genética , Sistema Enzimático do Citocromo P-450/genética , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Neoplasias/genética , RNA Mensageiro/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/sangue , Biópsia , Estudos de Casos e Controles , Sistema Enzimático do Citocromo P-450/sangue , DNA de Neoplasias/genética , DNA de Neoplasias/metabolismo , Raios gama/uso terapêutico , Expressão Gênica , Perfilação da Expressão Gênica , Gengiva/metabolismo , Gengiva/patologia , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Proteínas de Neoplasias/sangue , RNA Mensageiro/metabolismo , RNA Neoplásico/genética , RNA Neoplásico/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Uso de Tabaco/efeitos adversos
9.
Neoplasia ; 21(2): 197-205, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30616092

RESUMO

Smoking and alcohol intake are major risk factors in head and neck squamous cell carcinomas (HNSCCs). Although the link between TP53 mutation and smoking has been well established, very little is known about the link between acquired uniparental disomy (aUPD) and smoking and/or alcohol consumption or other clinical characteristics. We used TCGA genomic data to investigate whether smoking, alcohol intake, clinical and demographic variables, HPV status and TP53 mutation are associated with aUPD at specific chromosomal regions. In multivariate analysis, we found association between aUPD regions and risk factors and clinical variables of disease. aUPD regions on chromosome 4q, 5q, 9p, 9q, 13q, 17p and CDKN2A occurred significantly more often in patients with TP53-mutated HNSCC than in those with wild-type HNSCC, while aUPD regions on chromosome 9p and at CDKN2A were significantly more frequent in females than in males. Besides, aUPD occurred more frequent in HPV-positive than in HPV-negative samples with all HNSCC and larynx cancers on chromosome 9q 15q and 17p. Moreover, aUPD on CDKN2A region occurred more often in alcohol drinkers than nondrinkers in patients with all HNSCC and oral cavity cancers, while aUPD region on chromosome 5q occurred less in alcohol drinkers than nondrinkers in patients with all HNSCC and oral cavity cancers. Similarly, aUPD region on chromosome 5q occurred less in smokers than nonsmokers in patients with all HNSCC and oral cavity cancers. In conclusion, aUPD regions are not random, and certain regions are associated with risk factors for disease, and with TP53 mutation status.


Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Alelos , Infecções por Papillomavirus/complicações , Fumar/efeitos adversos , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Proteína Supressora de Tumor p53/genética , Dissomia Uniparental/genética , Bases de Dados Genéticas , Estudo de Associação Genômica Ampla , Humanos , Mutação , Gradação de Tumores , Estadiamento de Neoplasias , Polimorfismo de Nucleotídeo Único , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico
10.
Eur Arch Otorhinolaryngol ; 276(3): 857-864, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30607561

RESUMO

PURPOSE: The importance of occupational exposures in patients with head and neck squamous cell carcinomas (HNSCC) has received little attention. METHODS: In a single-center study, we prospectively characterized occupational exposures in 154 HNSCC cancer patients in a systematic occupational consultation and examined the association between most frequent exposures, HNSCC stage and localization. RESULTS: Patients occupied a mean of 3.3 different positions during their working life. The prevalence of asbestos, the most frequent exposure (46 patients; 29.9%) was higher than in the French population > 50 years. Other frequent exposures were solvents (n = 26; 16.9%) and silica (n = 19; 12.3%). For 37 patients (24%) a possible link was identified between occupational exposures and HNSCC. Duration of asbestos exposure was significantly higher (p = 0.04) in patients with hypopharyngeal and laryngeal cancer compared to other localizations. CONCLUSIONS: Occupational exposures are frequent in patients with HNSCC and should receive increased attention by physicians.


Assuntos
Neoplasias de Cabeça e Pescoço/etiologia , Doenças Profissionais/etiologia , Exposição Ocupacional/análise , Ocupações/estatística & dados numéricos , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Adulto , Idoso , Asbestos/análise , Asbestos/toxicidade , Carcinógenos/análise , Carcinógenos/toxicidade , Estudos de Casos e Controles , Feminino , Humanos , Neoplasias Laríngeas , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Prevalência , Estudos Retrospectivos , Solventes/análise , Solventes/toxicidade
11.
Esophagus ; 16(1): 98-106, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30145681

RESUMO

BACKGROUND: Esophageal adenocarcinoma (EAC) is frequently found on the right-anterior wall of the distal esophagus in short-segment Barrett's esophagus (SSBE) patients. However, the endoscopic characteristics of EAC in cases with long-segment BE (LSBE) and squamous cell carcinoma (ESCC) in the lower esophagus remain to be fully evaluated. Here, we determined the circumferential distribution and clinical characteristics of esophageal cancer occurring in the lower esophagus based on histological subtype. METHODS: We retrospectively reviewed the medical records of 150 patients with esophageal cancer (ESCC, n = 100; EAC, n = 50) diagnosed at our hospital or a related facility between January 2002 and June 2017, including information regarding endoscopic findings, etiology, and clinical parameters. RESULTS: Of the 100 patients with ESCC, 28 lesions were located in the lower esophagus, though characteristic circumferential distribution was not seen regardless of location. Those showed a greater frequency of smoking and drinking habit and gastric mucosal atrophy as compared to patients with EAC. Consistent with the previous reports, EAC in SSBE (n = 41) was frequently located on the right-anterior wall. Likewise, EAC at the esophagogastric junction (EGJ) in LSBE was frequently located on the right-anterior wall, while EAC distant from the EGJ showed no characteristic circumferential distribution. CONCLUSION: Our results showed no circumferential predilection for ESCC in the lower esophagus, suggesting that development of this type of lesion may be less affected by gastroesophageal reflux. In addition, EAC at the EGJ was frequently found on the right-anterior wall irrespective of BE length.


Assuntos
Esôfago de Barrett/patologia , Neoplasias Esofágicas/patologia , Lesões Pré-Cancerosas/patologia , Adenocarcinoma/etiologia , Adenocarcinoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Esôfago de Barrett/etiologia , Neoplasias Esofágicas/etiologia , Esofagite Péptica/complicações , Esofagoscopia , Feminino , Gastrite Atrófica/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/etiologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
12.
Future Oncol ; 15(6): 611-623, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30426780

RESUMO

AIM: To understand the treatment patterns and outcomes for stage IV squamous cell carcinoma of the head and neck, patients receiving second-line or later drug therapy. MATERIALS & METHODS: Real-world data were collected from 1152 patients in the USA, France, Germany and the UK through a retrospective chart analysis and patient-reported outcomes were collected using validated questionnaires in a subgroup of patients. RESULTS: Forty-four percent of patients had stage IVA/B disease. A total of 77, 19 and 3% of patients had received two, three and four plus lines of active drug treatment. Platinum- and cetuximab-based regimens were common at early treatment lines. Time to progression was short (5.2 months post first line), survival rates low and patient-reported health status poor. CONCLUSION: Novel therapies that could improve clinical and patient-reported outcomes would address a significant unmet need.


Assuntos
Padrões de Prática Médica , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Gerenciamento Clínico , Europa (Continente) , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Medidas de Resultados Relatados pelo Paciente , Retratamento , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Resultado do Tratamento
13.
Int J Cancer ; 144(11): 2635-2643, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-30183075

RESUMO

The objective of the review was to compare molecular and health effects of tobacco smoking using cigars, cigarillos, pipe and water pipe in relation to the effects of cigarette smoking. In this review we will focus on the upper respiratory tract. Mechanisms of interaction of tobacco smoke constituents after products other than cigarettes are similar to these associated with cigarette smoking. Carcinogenic activity was demonstrated for any type of tobacco smoking, although the risk of developing head and neck squamous cell carcinoma (HNSCC) remains lower in users of cigars, traditional pipe and water pipe as compared to cigarette smoking. Nevertheless, there is no way of safe tobacco smoking.


Assuntos
Neoplasias de Cabeça e Pescoço/epidemiologia , Sistema Respiratório/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Produtos do Tabaco/efeitos adversos , Fumar Tabaco/efeitos adversos , Neoplasias de Cabeça e Pescoço/etiologia , Humanos , Incidência , Sistema Respiratório/patologia , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Fumar Tabaco/tendências
14.
Biometrics ; 75(1): 202-209, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30203414

RESUMO

MicroRNAs (miRNAs) are small non-coding RNAs that function as regulators of gene expression. In recent years, there has been a tremendous interest among researchers to investigate the role of miRNAs in normal as well as in disease processes. To investigate the role of miRNAs in oral cancer, we analyse expression levels of miRNAs to identify miRNAs with statistically significant differential expression in cancer tissues. In this article, we propose a novel Bayesian hierarchical model of miRNA expression data. Compelling evidence has demonstrated that the transcription process of miRNAs in the human genome is a latent process instrumental for the observed expression levels. We take into account positional clustering of the miRNAs in the analysis and model the latent transcription phenomenon nonparametrically by an appropriate Gaussian process. For the purpose of testing, we employ a novel Bayesian multiple testing method where we mainly focus on utilizing the dependence structure between the hypotheses for better results, while also ensuring optimality in many respects. Indeed, our non-marginal method yielded results in accordance with the underlying scientific knowledge which are found to be missed by the very popular Benjamini-Hochberg method.


Assuntos
Teorema de Bayes , Análise por Conglomerados , Redes Reguladoras de Genes , MicroRNAs/genética , Estudos de Casos e Controles , Interpretação Estatística de Dados , Perfilação da Expressão Gênica , Humanos , Distribuição Normal , Reação em Cadeia da Polimerase , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fumar Tabaco/efeitos adversos
15.
Oral Oncol ; 87: 138-143, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30527229

RESUMO

OBJECTIVE: Several studies have shown a higher prevalence of hepatitis C virus (HCV) infection among patients with head and neck cancer (HNC) compared to the general population. In Brazil, the prevalence of HCV infection is considered low (1.38%). The aim of this study was to determine HCV prevalence and how this can modify outcomes of patients with HNC. STUDY DESIGN: Retrospective cohort. METHODS: Patients with a diagnosis of malignant neoplasm in the head and neck (HN) region and who had serology performed for HCV were included. Patients were classified into two groups: head and neck squamous cell carcinoma (HNSCC) and other head and neck malignant neoplasms (OHNMN). Descriptive statistics were performed for all variables of interest. Means were compared using ANOVA and proportions using chi-square tests. Survival data were compared by Kaplan-Meier curves and log-rank test. RESULTS: Global HCV prevalence in patients with HNC was 7.8%, reaching 12.8% in HNSCC and 3.4% in OHNMN (p = 0.003). There was a higher risk of developing a second primary neoplasm in HNSCC compared to OHNMN patients (20.6% versus 4.6%; p = 0.001). The mean survival was not different between HCV-positive and HCV-negative patients (6.0 years versus 6.6 years, respectively, p = 0.516). CONCLUSION: The prevalence of HCV infection was higher in HNC patients compared to the general Brazilian population. It seems reasonable to consider that HCV infection is associated with an increased risk of HNC, but HCV infection does not worsens the prognosis of HNC patients.


Assuntos
Neoplasias de Cabeça e Pescoço/mortalidade , Hepatite C/epidemiologia , Segunda Neoplasia Primária/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto , Idoso , Brasil/epidemiologia , Ensaio de Imunoadsorção Enzimática , Feminino , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/etiologia , Hepacivirus/imunologia , Hepacivirus/isolamento & purificação , Hepatite C/sangue , Hepatite C/complicações , Anticorpos Anti-Hepatite C/sangue , Anticorpos Anti-Hepatite C/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Segunda Neoplasia Primária/sangue , Prevalência , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Testes Sorológicos , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Análise de Sobrevida
16.
Crit Rev Oncog ; 23(3-4): 161-171, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30311572

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is an immunosuppressive disease with multiple mechanisms to impair immune-mediated recognition and control of tumor cell proliferation and metastasis. Based on successes experienced with cancer immunotherapy in the treatment of other solid tumors, considerable efforts are underway to develop immunotherapeutics that can enhance the host antitumor response to HNSCC. Promising results in preclinical studies and early clinical trials have been reported, prompting the FDA to approve the use of the immune checkpoint PD-1 receptor antagonist pembrolizumab for the treatment of platinum-refractory recurrent or metastatic HNSCC in 2016. Ongoing clinical trials are investigating the use of various immunotherapies, such as vaccines, adoptive T-cell transfer, and immune modulating antibodies alone or in conjunction with traditional treatment modalities, to achieve more efficacious, more durable, and less toxic treatments. In this article, we provide a basic review of the role of the immune system in developing malignancy, and we discuss some notable mechanisms of immune evasion in HNSCC. We highlight current approaches and published clinical results of immunotherapy in the treatment of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia , Animais , Biomarcadores Tumorais , Vacinas Anticâncer/imunologia , Vacinas Anticâncer/uso terapêutico , Terapia Combinada , Neoplasias de Cabeça e Pescoço/diagnóstico , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia/métodos , Imunoterapia Adotiva/métodos , Terapia de Alvo Molecular , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/genética
17.
Crit Rev Oncog ; 23(3-4): 235-245, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30311577

RESUMO

Head and neck squamous cell carcinoma (HNSCC) manifests in the mucosal epithelial lining of the oral cavity, oropharynx, hypopharynx, nasopharynx or larynx and has a tremendous disease burden worldwide. Smoking and alcohol consumption were once major risk factors, but HPV-associated infection has emerged as the major contributor to HNSCC occurrence in developed countries. Circulating biomarker evaluations in biofluids, also known as liquid biopsy, are an attractive alternative for cancer screening as they are minimally invasive, potentially low cost, and easily repeatable on a serial basis. This review summarizes the current knowledge and potential of assessing circulating blood and salivary HPV DNA and HPV antibodies for the surveillance of HPV-positive HNSCC. Additionally, the biological underpinnings of the presence and relevance of circulating HPV DNA is discussed.


Assuntos
Biomarcadores Tumorais , DNA Tumoral Circulante , Infecções por Papillomavirus/complicações , Saliva , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Anticorpos Antivirais/imunologia , Feminino , Humanos , Biópsia Líquida/métodos , Masculino , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Vigilância da População , Saliva/química , Saliva/metabolismo
19.
Clin Cancer Res ; 24(23): 6001-6014, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30087144

RESUMO

PURPOSE: Following cytotoxic therapy, 70% of patients with human papillomavirus (HPV)-positive oropharyngeal head and neck squamous cell carcinoma (HNSCC) are alive at 5 years compared with 30% of those with similar HPV-negative cancer. Loss of TGFß signaling is a poorly studied consequence of HPV that could contribute to patient outcome by compromising DNA repair. EXPERIMENTAL DESIGN: Human HNSCC cell lines (n = 9), patient-derived xenografts (n = 9), tissue microarray (n = 194), TCGA expression data (n = 279), and primary tumor specimens (n = 10) were used to define the relationship between TGFß competency, response to DNA damage, and type of DNA repair. RESULTS: Analysis of HNSCC specimens in situ and in vitro showed that HPV associated with loss of TGFß signaling that increased response to radiation or cisplatin. TGFß suppressed miR-182, which inhibited both BRCA1, necessary for homologous recombination repair (HRR), and FOXO3, required for ATM kinase activity. TGFß signaling blockade by either HPV or inhibitors released miR182 control, compromised HRR and increased response to PARP inhibition. Antagonizing miR-182 rescued the HRR deficit in HPV-positive cells. Loss of TGFß signaling unexpectedly increased repair by error prone, alternative end-joining (alt-EJ). CONCLUSIONS: HPV-positive HNSCC cells are unresponsive to TGFß. Abrogated TGFß signaling compromises repair by HRR and increases reliance on alt-EJ, which provides a mechanistic basis for sensitivity to PARP inhibitors. The effect of HPV in HNSCC provides critical validation of TGFß's role in DNA repair proficiency and further raises the translational potential of TGFß inhibitors in cancer therapy.


Assuntos
Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Reparo de DNA por Recombinação , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Modelos Animais de Doenças , Citometria de Fluxo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
20.
Med Mal Infect ; 48(8): 503-508, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29887186

RESUMO

OBJECTIVES: Head and neck squamous cell carcinoma (HNSCC), mainly due to smoking, is one of the leading causes of cancer deaths. However, an increasing number of tumors - especially oropharyngeal cancer - are reported in non-smokers in association with the human papillomavirus (HPV). As HIV-infected individuals are particularly at risk of HPV-related disease, we aimed to describe the burden of HNSCC in this population. METHODS: Retrospective chart review of patients from HIV clinics diagnosed with HNSCC between 2004 and 2014. Case patients were defined using the International Classification of Disease for Oncology (3rd edition). Age at HIV diagnosis and time from HIV diagnosis to HNSCC diagnosis were collected. Oropharyngeal cancers were considered as potentially HPV-related cancers, and their prevalence was compared with other HNSCCs over time. RESULTS: The 286 patients enrolled in the study had a median age at HNSCC diagnosis of 52 years; 84% were males and 68% had a history of smoking. The oropharynx was the most frequent site (41%), followed by cancer of the oral cavity (31%), larynx (22%), and hypopharynx (7%). The prevalence (and proportion) of potentially HPV-related cancers increased significantly over time with a mean of 0.78 additional case patient per year. CONCLUSION: The prevalence of HNSCC is modest compared with other cancers in HIV-infected individuals. The prevalence of oropharynx carcinoma, a potentially HPV-related carcinoma, seems to increase over time. Even if tobacco may be an important contributor, the role of HPV in HIV-infected individuals presenting with HNSCC should be investigated.


Assuntos
Infecções por HIV/complicações , Neoplasias Hipofaríngeas/epidemiologia , Neoplasias Hipofaríngeas/etiologia , Neoplasias Laríngeas/epidemiologia , Neoplasias Laríngeas/etiologia , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/etiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/epidemiologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/etiologia , Feminino , França/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
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