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1.
Anticancer Res ; 41(11): 5557-5568, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34732426

RESUMO

BACKGROUND/AIM: We investigated the prevalence of human papillomavirus (HPV) in a prospective cohort of patients with squamous cell carcinoma of the oral cavity (OSCC) using both p16INK4a and HPV DNA, i.e., double positivity, as a definition criterion. Additionally, we examined the association of HPV with survival. PATIENTS AND METHODS: Samples from 280 OSCC patients were analyzed for HPV-positivity using p16INK4a immunohistochemistry (IHC) and in situ hybridization (ISH)/LCD arrays, for HPV low and high-risk types. Only patients positive for both p16INK4a and HPV DNA were considered as HPV-positive. Survival probabilities and 95% confidence intervals were estimated using the Kaplan-Meier method. Cox proportional hazards models were used to assess HPV association with disease-free survival (DFS), cause-specific survival (CSS) and overall survival (OS) in a competing risks scenario. RESULTS: Specimen from 30 (10.7%) patients were p16+ and HPV DNA+, while 31 (11.0%) were either p16+ or HPV DNA+ only. OS probabilities at five years for HPV-positive and -negative groups were 50.9% (35.4%-73.1%) and 52.9% (47.0%-59.5%), respectively. HPV double positivity influenced neither OS, CSS nor DFS: HR=0.84 (0.43-1.63), 1.64 (0.76-3.54) and 1.13 (0.55-2.35), respectively. CONCLUSION: In contrast to oropharyngeal cancer, the prevalence of HPV in OSCC is low and the presence of HPV does not influence survival outcomes. Hence, there is no evidence to support a parallel transfer of therapy regimen for HPV-positive OPC to OSCC, in terms of therapy de-escalation and/or vaccination.


Assuntos
Alphapapillomavirus/genética , Biomarcadores Tumorais/análise , Inibidor p16 de Quinase Dependente de Ciclina/análise , DNA Viral/genética , Neoplasias Bucais/diagnóstico , Infecções por Papillomavirus/diagnóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Idoso , Intervalo Livre de Doença , Feminino , Alemanha/epidemiologia , Testes de DNA para Papilomavírus Humano , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/química , Neoplasias Bucais/terapia , Neoplasias Bucais/virologia , Infecções por Papillomavirus/terapia , Infecções por Papillomavirus/virologia , Valor Preditivo dos Testes , Prevalência , Carcinoma de Células Escamosas de Cabeça e Pescoço/química , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Fatores de Tempo
2.
BMC Cancer ; 21(1): 1075, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600526

RESUMO

BACKGROUND: Monitoring circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), known as liquid biopsies, continue to be developed as diagnostic and prognostic markers for a wide variety of cancer indications, mainly due to their minimally invasive nature and ability to offer a wide range of phenotypic and genetic information. While liquid biopsies maintain significant promising benefits, there is still limited information regarding the kinetics of ctDNA and CTCs following radiation therapy which remains a vital treatment modality in head and neck cancers. This study aims to describe the kinetics of ctDNA and CTCs following radiation exposure in a preclinical rabbit model with VX2 induced buccal carcinoma. METHODS: Seven rabbits were inoculated with VX2 cells in the buccal mucosa and subjected to radiation. At selected time points, blood sampling was performed to monitor differing levels of ctDNA and CTC. Plasma ctDNA was measured with quantitative PCR for papillomavirus E6 while CTCs were quantified using an immunomagnetic nanoparticles within a microfluidic device. Comparisons of CTC detection with EpCAM compared to multiple surface markers (EGFR, HER2 and PSMA) was evaluated and correlated with the tumor size. RESULTS: Plasma ctDNA reflects the overall tumor burden within the animal model. Analysis of correlations between ctDNA with tumor and lymph node volumes showed a positive correlation (R = 0.452 and R = 0.433 [p < 0.05]), respectively. Over the course of treatment, ctDNA levels declined and quickly becomes undetectable following tumor eradication. While during the course of treatment, ctDNA levels were noted to rise particularly upon initiation of radiation following scheduled treatment breaks. Levels of CTCs were observed to increase 1 week following inoculation of tumor to the primary site. For CTC detection, the use of multiple surface markers showed a greater sensitivity when compared to detection using only EpCAM. Plasma CTC levels remained elevated following radiation therapy which may account for an increased shedding of CTCs following radiation. CONCLUSION: This study demonstrates the utility of ctDNA and CTCs detection in response to radiation treatment in a preclinical head and neck model, allowing for better understanding of liquid biopsy applications in both clinical practice and research development.


Assuntos
Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/radioterapia , Ácidos Nucleicos Livres/sangue , Neoplasias Bucais/sangue , Neoplasias Bucais/radioterapia , Animais , Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/induzido quimicamente , DNA Tumoral Circulante/sangue , Papillomavirus de Coelho Cottontail , Molécula de Adesão da Célula Epitelial/sangue , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/induzido quimicamente , Neoplasias de Cabeça e Pescoço/radioterapia , Separação Imunomagnética/métodos , Biópsia Líquida/métodos , Masculino , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/virologia , Nanopartículas , Transplante de Neoplasias , Fases de Leitura Aberta , Coelhos , Dosagem Radioterapêutica , Carga Tumoral
3.
Nat Commun ; 12(1): 5945, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642315

RESUMO

Although several oropharyngeal cancer (OPC) susceptibility loci have been identified, most previous studies lacked detailed information on human papillomavirus (HPV) status. We conduct a genome-wide analysis by HPV16 serology status in 4,002 oral cancer cases (OPC and oral cavity cancer (OCC)) and 5,256 controls. We detect four susceptibility loci pointing to a distinct genetic predisposition by HPV status. Our most notable finding in the HLA region, that is now confirmed to be specific of HPV(+)OPC risk, reveal two independent loci with strong protective effects, one refining the previously reported HLA class II haplotype association. Antibody levels against HPV16 viral proteins strongly implicate the protective HLA variants as major determinants of humoral response against L1 capsid protein or E6 oncoprotein suggesting a natural immune response against HPV(+)OPC promoted by HLA variants. This indicates that therapeutic vaccines that target E6 and attenuate viral response after established HPV infections might protect against HPV(+)OPC.


Assuntos
Antígenos HLA/imunologia , Papillomavirus Humano 16/imunologia , Imunidade Humoral , Neoplasias Bucais/imunologia , Neoplasias Orofaríngeas/imunologia , Infecções por Papillomavirus/imunologia , Idoso , Anticorpos Antivirais/biossíntese , Proteínas do Capsídeo/genética , Proteínas do Capsídeo/imunologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Antígenos HLA/classificação , Antígenos HLA/genética , Haplótipos , Papillomavirus Humano 16/patogenicidade , Humanos , Masculino , Metanálise como Assunto , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Proteínas Oncogênicas Virais/genética , Proteínas Oncogênicas Virais/imunologia , Neoplasias Orofaríngeas/genética , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia , Locos de Características Quantitativas , Proteínas Repressoras/genética , Proteínas Repressoras/imunologia , Fatores de Risco , Fumar/fisiopatologia
4.
Viruses ; 13(7)2021 07 11.
Artigo em Inglês | MEDLINE | ID: mdl-34372545

RESUMO

Human papillomavirus (HPV) imposes an increased risk of developing cervical, anal and oropharyngeal cancer. In the Western world, HPV infection is currently the major cause of oropharyngeal cancer. The effectiveness of HPV vaccines for oral or oropharyngeal HPV infection is yet to be determined. This study conducted a systematic literature search in Pubmed and Embase. Studies investigating the impact of HPV vaccines on oral or oropharyngeal HPV infection were enrolled. This review reports the relative prevention percentage (RPP), including a risk of bias assessment as well as a quality assessment study. Nine studies were included (48,777 participants): five cross-sectional studies; one randomized community trial study (RCT); one longitudinal cohort study; and two case-control studies. A significant mean RPP of 83.9% (66.6-97.8%) was calculated from the cross-sectional studies, 82.4% in the included RCT and 83% in the longitudinal cohort study. Further, two case-control studies that measured antibody response in participants immunized with HPV vaccines were included. Respectively, 100% and 93.2% of participants developed HPV-16 Immunoglobulin G (IgG) antibodies in oral fluids post-vaccination. Analysis of the studies identified a significant decrease in vaccine-type oral or oropharyngeal HPV infections in study participants immunized with HPV vaccines across study designs and heterogenous populations. Further, a significant percentage of participants developed IgG antibodies in oral fluid post-vaccination.


Assuntos
Infecções por Papillomavirus/prevenção & controle , Vacinas contra Papillomavirus/farmacologia , Alphapapillomavirus/patogenicidade , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Estudos Longitudinais , Masculino , Boca/virologia , Neoplasias Bucais/prevenção & controle , Neoplasias Bucais/virologia , Neoplasias Orofaríngeas/prevenção & controle , Neoplasias Orofaríngeas/virologia , Orofaringe/virologia , Papillomaviridae/imunologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/metabolismo , Vacinas contra Papillomavirus/metabolismo , Profilaxia Pré-Exposição/métodos , Vacinação
5.
Sci Rep ; 11(1): 14943, 2021 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-34294795

RESUMO

The ability of cancer cells to undergo partial-epithelial mesenchymal transition (p-EMT), rather than complete EMT, poses a higher metastatic risk. Although Fusobacterium nucleatum mainly inhabits in oral cavity, attention has been focused on the F. nucleatum involvement in colorectal cancer development. Here we examined the p-EMT regulation by F. nucleatum in oral squamous cell carcinoma (OSCC) cells. We cultured OSCC cells with epithelial, p-EMT or EMT phenotype with live or heat-inactivated F. nucleatum. Expression of the genes involved in epithelial differentiation, p-EMT and EMT were examined in OSCC cells after co-culture with F. nucleatum by qPCR. Cell growth and invasion of OSCC cells were also examined. Both live and heat-inactivated F. nucleatum upregulated the expression of p-EMT-related genes in OSCC cells with epithelial phenotype, but not with p-EMT or EMT phenotype. Moreover, F. nucleatum promoted invasion of OSCC cells with epithelial phenotype. Co-culture with other strains of bacteria other than Porphyromonas gingivalis did not alter p-EMT-related genes in OSCC cells with epithelial phenotype. F. nucleatum infection may convert epithelial to p-EMT phenotype via altering gene expression in OSCC. Oral hygiene managements against F. nucleatum infection may contribute to reduce the risk for an increase in metastatic ability of OSCC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/virologia , Infecções por Fusobacterium/complicações , Fusobacterium nucleatum/patogenicidade , Neoplasias Bucais/virologia , Carcinoma de Células Escamosas/genética , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Transição Epitelial-Mesenquimal , Infecções por Fusobacterium/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Bucais/genética , Metástase Neoplásica , Higiene Bucal
6.
BMC Cancer ; 21(1): 688, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34112111

RESUMO

BACKGROUND: Low-risk human papillomavirus (HPV), such as types 6 and 11, is considered non-oncogenic, but these types have been detected in oral cancer tissue samples, suggesting their possible involvement in oral carcinogenesis. Because double infection of high-risk HPV and Epstein-Barr virus (EBV) is known to be involved in oral carcinogenesis, we hypothesized that low-risk HPV and EBV co-infection can transform the oral cells. To verify our hypothesis, we evaluated the transformation activity of cell lines expressing both low-risk HPV E6/E7 and EBV LMP-1. METHODS: We transduced HPV6, 11 and 16 E6/E7 genes and EBV LMP-1 gene into primary mouse embryonic fibroblasts. The cell lines were examined for indices of transformation activity such as proliferation, induction of DNA damage, resistance to apoptosis, anchorage-independent growth, and tumor formation in nude mice. To evaluate the signaling pathways involved in transformation, NF-κB and p53 activities were analyzed. We also assessed adhesion signaling molecules associated with anchorage-independent growth such as MMP-2, paxillin and Cat-1. RESULTS: Co-expression of low-risk HPV6 E6 and EBV LMP-1 showed increased cell proliferation, elevated NF-κB activity and reduced p53 induction. Moreover, co-expression of low-risk HPV6 E6 and EBV LMP-1 induced DNA damage, escaped from apoptosis under genotoxic condition and suppression of DNA damage response (DDR). Co-expression of low-risk HPV11 E6/E7 and EBV LMP-1 demonstrated similar results. However, it led to no malignant characteristics such as anchorage-independent growth, invasiveness and tumor formation in nude mice. Compared with the cells co-expressing high-risk HPV16 E6 and EBV LMP-1 that induce transformation, co-expression of low-risk HPV6 E6 and EBV LMP-1 was associated with low MMP-2, paxillin and Cat-1 expression. CONCLUSIONS: The co-expression of low-risk HPV E6/E7 and EBV LMP-1 does not induce malignant transformation, but it allows accumulation of somatic mutations secondary to increased DNA damage and suppression of DDR. Thus, double infection of low-risk HPV and EBV could lead to precancerous lesions.


Assuntos
Coinfecção/patologia , Infecções por Vírus Epstein-Barr/patologia , Neoplasias Bucais/genética , Infecções por Papillomavirus/patologia , Lesões Pré-Cancerosas/patologia , Animais , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/patologia , Coinfecção/genética , Coinfecção/virologia , Dano ao DNA , Reparo do DNA , Modelos Animais de Doenças , Infecções por Vírus Epstein-Barr/virologia , Feminino , Fibroblastos , Herpesvirus Humano 4/patogenicidade , Interações Hospedeiro-Patógeno/genética , Papillomavirus Humano 11/patogenicidade , Papillomavirus Humano 6/metabolismo , Humanos , Camundongos , Mucosa Bucal/patologia , Mucosa Bucal/virologia , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Mutação , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/virologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/virologia , Cultura Primária de Células , Proteínas da Matriz Viral/metabolismo
7.
Viruses ; 13(4)2021 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-33810374

RESUMO

This study is focused on the epidemiological characteristics and biomolecular mechanisms that lead to the development of precancerous and cancerous conditions of oral lesions related to Human Papilloma Virus (HPV) infections. Current evidence from the literature demonstrates the role of HPV in potentially malignant oral disorders. Therefore, the underlying biomolecular processes can give arise, or contribute to, benign lesions as well as to oral carcinogenesis.


Assuntos
Carcinogênese/genética , Neoplasias Bucais/virologia , Papillomaviridae/genética , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Humanos , Microbiota , Boca/patologia , Boca/virologia , Neoplasias Bucais/genética
8.
Viruses ; 13(4)2021 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-33916990

RESUMO

Papillomaviruses (PVs) are a diverse group of host species-specific DNA viruses, etiologically linked with various benign and malignant neoplasms of cutaneous and mucosal epithelia. Here, we describe the detection and characterization of the first two PVs naturally infecting Japanese macaques (Macaca fuscata), including the determination of their etiological association(s) with the development of original neoplasms. The molecular and phylogenetic analyses were performed on complete genome sequences of Macaca fuscata PV types 1 (MfuPV1) and 2 (MfuPV2), which were completely sequenced in samples of a malignant oral tumor and benign anogenital neoplasm of Japanese macaques, respectively. Subsequently, two type-specific quantitative real-time PCRs were developed to estimate viral loads of MfuPV1 and MfuPV2 and to evaluate their etiological roles. The in silico molecular analyses revealed that both viral genomes encode characteristic PV proteins with conserved functional domains and have a non-coding genomic region with regulatory sequences to regulate and complete the viral life cycle. However, additional experimental evidence is needed to finally confirm the presence and biological functionality of the molecular features of both novel PVs. While MfuPV1, together with PVs identified in other macaques, is classified into the Alphapapillomavirus (Alpha-PV) species 12, MfuPV2 is most likely a representative of the novel viral species within the Alpha-PV genus. Their relatively high viral loads suggest that both PVs are etiologically linked with the development of the original neoplasms.


Assuntos
Neoplasias do Ânus/veterinária , Neoplasias dos Genitais Femininos/veterinária , Neoplasias dos Genitais Masculinos/veterinária , Macaca fuscata/virologia , Neoplasias Bucais/veterinária , Neoplasias/veterinária , Papillomaviridae/classificação , Papillomaviridae/genética , Infecções por Papillomavirus/veterinária , Animais , Neoplasias do Ânus/virologia , Sequência de Bases , Feminino , Neoplasias dos Genitais Femininos/virologia , Neoplasias dos Genitais Masculinos/virologia , Genoma Viral , Masculino , Boca/virologia , Neoplasias Bucais/virologia , Neoplasias/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Filogenia , Carga Viral
9.
Int J Cancer ; 149(2): 420-430, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-33634865

RESUMO

The prognostic impact of human papillomavirus (HPV) in oropharyngeal cancer is generally acknowledged, and HPV-status is assessed routinely in clinical practice. Paradoxically, while the oral cavity seems the predilection site for productive HPV-infections, figures on HPV-attribution in oral cavity squamous cell carcinoma (OCSCC) differ widely, and prognostic impact is uncertain. Major obstacles are the lack of reproducible assays to detect HPV in nonoropharyngeal cancers, the relatively small cohorts studied and consequently the shortfall of convincing data. In our study, we used a validated, nucleic acid-based workflow to assess HPV-prevalence in a consecutive cohort of 1016 OCSCCs, and investigated its prognostic impact. In parallel, we analyzed p16-immunohistochemistry (p16-IHC) as surrogate marker for transforming HPV-infection and independent prognosticator. All OCSCC-patients diagnosed between 2008 and 2014 at two Dutch university medical centers were included (N = 1069). Formalin-fixed, paraffin-embedded (FFPE)-samples of 1016 OCSCCs could be retrieved. Punch biopsies were taken from the tumor area in the FFPE-blocks and tested for HPV. P16-IHC was performed on 580 OCSCCs, including all HPV-positive tumors. From 940 samples (92.5%), nucleic acids were of sufficient quality for HPV-testing. In total, 21 (2.2%) OCSCCs were HPV DNA-positive. All HPV DNA-positive tumors were E6 mRNA-positive and considered as true HPV-positive. There was no difference in survival between HPV-positive and HPV-negative OCSCCs. In total, 46 of 580 (7.9%) OCSCCs were p16-immunopositive, including all HPV-positive tumors. Survival was comparable in p16-positive and p16-negative OCSCCs. To conclude, HPV-prevalence is very low in OCSCC and neither HPV-status nor p16-status affects outcome. Based on these data, determining HPV-status in OCSCC seems irrelevant for clinical management.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Papillomavirus Humano 16/isolamento & purificação , Neoplasias Bucais/diagnóstico , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/epidemiologia , Proteínas Repressoras/genética , Idoso , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Papillomavirus Humano 16/genética , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/metabolismo , Prevalência , Prognóstico , Caracteres Sexuais , Análise de Sobrevida
10.
Epidemiol Health ; 43: e2021013, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33541009

RESUMO

OBJECTIVES: Cancer is a multi-factorial disease, with various intrinsic and environmental factors contributing to its occurrence. Human papillomavirus (HPV) has been associated with the occurrence of many cancers. India severely suffers from 3 HPV-associated cancers (cervical cancer, oral cancer, and oropharyngeal cancer). Hence, the present study aimed to evaluate the HPV burden in these 3 cancers among patients from the western region of India. METHODS: DNA was isolated from samples from 400 cervical cancer, 127 oral cancer, and 75 oropharyngeal cancer patients. Polymerase chain reaction was performed using degenerate primers for HPV infection. RESULTS: Overall, HPV infection was observed in 87% of cervical cancer cases, 12.5% of oral cancer cases, and 26.7% of oropharyngeal cancer cases when analyzed with a cumulative detection method using the MY 09/11, GP 5+/6+, and CP I/II primer sets. CONCLUSIONS: A significant prevalence of HPV infection was detected in all 3 cancers using the degenerate primer sets. This finding implies that testing for HPV infection using multiple primer sets is crucial for determining its actual prevalence in various malignancies.


Assuntos
Alphapapillomavirus/isolamento & purificação , Neoplasias Bucais/virologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/virologia , Adulto , Alphapapillomavirus/genética , DNA Viral/isolamento & purificação , Feminino , Humanos , Índia/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Neoplasias Orofaríngeas/epidemiologia , Reação em Cadeia da Polimerase , Neoplasias do Colo do Útero/epidemiologia
11.
Chem Biol Interact ; 333: 109321, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33186600

RESUMO

HPV infections in the oral cavity that progress to cancer are on the increase in the USA. Model systems to study co-factors for progression of these infections are lacking as HPVs are species-restricted and cannot grow in preclinical animal models. We have recently developed a mouse papillomavirus (MmuPV1) oral mucosal infection model that provides opportunities to test, for the first time, the hypothesis that tobacco carcinogens are co-factors that can impact the progression of oral papillomas to squamous cell carcinoma (SCC). Four cohorts of mice per sex were included: (1) infected with MmuPV1 and treated orally with DMSO-saline; (2) infected with MmuPV1 and treated orally with the tobacco carcinogen, dibenzo[def,p]chrysene (DBP); (3) uninfected and treated orally with DMSO-saline, and (4) uninfected and treated orally with DBP. Oral swabs were collected monthly for subsequent assessment of viral load. Oral tissues were collected for in situ viral DNA/RNA detection, viral protein staining, and pathological assessment for hyperplasia, papillomas and SCC at study termination. We observed increased rates of SCC in oral tissue infected with MmuPV1 and treated with DBP when compared to mice treated with DBP or virus individually, each of which showed minimal disease. Virally-infected epithelium showed strong levels of viral DNA/RNA and viral protein E4/L1 staining. In contrast, areas of SCC showed reduced viral DNA staining indicative of lower viral copy per nucleus but strong RNA signals. Several host markers (p120 ctn, p53, S100A9) were also examined in the mouse oral tissues; of particular significance, p120 ctn discriminated normal un-infected epithelium from SCC or papilloma epithelium. In summary, we have confirmed that our infection model is an excellent platform to assess the impact of co-factors including tobacco carcinogens for oral PV cancerous progression. Our findings can assist in the design of novel prevention/treatment strategies for HPV positive vs. HPV negative disease.


Assuntos
Crisenos/toxicidade , Progressão da Doença , Poluentes Ambientais/toxicidade , Neoplasias Bucais/patologia , Papillomaviridae/fisiologia , Fumaça/efeitos adversos , Tabaco/efeitos adversos , Animais , Carcinogênese/efeitos dos fármacos , Feminino , Genoma Viral/genética , Masculino , Camundongos , Neoplasias Bucais/virologia , Papillomaviridae/genética , Caracteres Sexuais , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
12.
Oral Oncol ; 112: 105084, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33181417

RESUMO

OBJECTIVES: The impact of regulatory T (Treg) cells as a prognostic factor of survival in head and neck squamous cell carcinoma (HNSCC) remains controversial. We aimed to evaluate the prognostic value of Treg cells in patients with HNSCC through a meta-analysis. MATERIALS AND METHODS: Through a literature search in PubMed, Embase, and Cochrane, we included 11 articles in this meta-analysis and investigated the effect of Treg cell level on the survival of patients with HNSCC. Also, we performed a subgroup analysis according to the study sample (blood vs. tumor tissue), primary tumor site, HPV infectivity, or Treg cell marker. RESULTS: High levels of circulating Treg cells in the peripheral blood of patients with HNSCC can significantly increase the disease specific survival rate of patients. Moreover, subgroup analysis showed that high levels of Treg in peripheral blood were significantly associated with better disease specific survival in patients with oral cancer, a subsite of HNSCC, but not in those with other head and neck subsite. Positivity of HPV infection did not influence the prognosis of patients with HNSCC. CONCLUSION: Increase in the levels of circulating Treg cells in peripheral blood can be a prognostic factor of survival in patients with oral cancer.


Assuntos
Neoplasias Bucais/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Linfócitos T Reguladores/citologia , Fatores de Transcrição Forkhead/análise , Humanos , Neoplasias Bucais/sangue , Neoplasias Bucais/imunologia , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/complicações , Prognóstico , Viés de Publicação , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Taxa de Sobrevida , Linfócitos T Reguladores/química
13.
Oral Oncol ; 112: 105093, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33232879

RESUMO

Gender and race disparities in head and neck squamous cell carcinoma (HSNCC) survival are independently well documented, but no prior studies have examined the joint effect of these factors on HSNCC outcomes. We aim to comprehensively estimate the effect of gender and race on overall survival in HNSCC. We constructed a retrospective cohort from the National Cancer Database for primary HNSCC of the larynx, hypopharynx, oral cavity, and oropharynx from 2010 to 2015. We used Kaplan-Meier curves and Cox proportional hazards regressions to calculate hazard ratios adjusting for treatment type, age, insurance, staging classifications, and comorbidities. Oral cavity cancer was significantly more common among Hispanic and White females compared to other sites. Female non-oropharyngeal HNSCC cases had better five-year overall survival than males (56.3% versus 54.4%, respectively), though Black females (52.8%) had poorer survival than both White (56.2%) and Hispanic (57.9%) males. There were significant differences in oropharyngeal cancer by HPV status. Notably, Black females with HPV-positive oropharyngeal OPSCC had far worse survival than any other race and gender group. These results persisted even when adjusting for potential mediating factors. Clearly gender is a significant prognosticator for HNSCC and has meaningful interactions with race. The distinct site distributions across gender and race reveal important insights into HNSCC among females. Taking into account these gender disparities while considering race is essential to providing appropriate care to head and neck patients and accurately counselling these individuals on prognosis and outcomes.


Assuntos
Fatores Sexuais , Carcinoma de Células Escamosas de Cabeça e Pescoço/etnologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Grupo com Ancestrais do Continente Africano , Fatores Etários , Idoso , Grupo com Ancestrais do Continente Europeu , Feminino , Hispano-Americanos , Humanos , Neoplasias Hipofaríngeas/etnologia , Neoplasias Hipofaríngeas/mortalidade , Neoplasias Hipofaríngeas/patologia , Neoplasias Hipofaríngeas/virologia , Renda , Cobertura do Seguro/estatística & dados numéricos , Estimativa de Kaplan-Meier , Neoplasias Laríngeas/etnologia , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/etnologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Neoplasias Orofaríngeas/etnologia , Neoplasias Orofaríngeas/mortalidade , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Papillomaviridae , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
14.
Adv Exp Med Biol ; 1287: 105-122, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33034029

RESUMO

The NOTCH pathway is critical for the development of many cell types including the squamous epithelium lining of cutaneous and mucosal surfaces. In genetically engineered mouse models, Notch1 acts as one of the first steps to commit basal keratinocytes to terminally differentiate. Similarly, in human head and neck squamous cell cancers (HNSCCs), NOTCH1 is often lost consistent with its essential tumor-suppressive role for initiating keratinocyte differentiation. However, constitutive NOTCH1 activity in the epithelium results in expansion of the spinous keratinocyte layers and impaired terminal differentiation is consistent with the role of NOTCH1 as an oncogene in other cancers, especially in T-cell acute lymphoblastic leukemia. We have previously observed that NOTCH1 plays a dual role as both a tumor suppressor and oncogene, depending on the mutational context of the tumor. Namely, gain or loss or NOTCH1 activity promotes the development of human papillomavirus (HPV)-associated cancers. The additional HPV oncogenes likely disrupt the tumor-suppressive activities of NOTCH and enable the oncogenic pathways activated by NOTCH to promote tumor growth. In this review, we detail the role of NOTCH pathway in head and neck cancers with a focus on HPV-associated cancers.


Assuntos
Carcinogênese , Neoplasias Bucais/metabolismo , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/metabolismo , Receptores Notch/metabolismo , Transdução de Sinais , Animais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/virologia , Humanos , Infecções por Papillomavirus/virologia
15.
Asian Pac J Cancer Prev ; 21(11): 3349-3355, 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33247695

RESUMO

OBJECTIVES: To identify the prevalence of high-risk human papillomavirus (HPV) genotypes 16 and 18 among patients with oral squamous cell carcinoma (OSCC) in Thailand and investigate the associations of p16 expression and HPV16/18 with the demographic, clinicopathologic, and risk parameters. MATERIALS AND METHODS: A total of 403 formalin-fixed paraffin-embedded OSCC specimens from four centers in four regions were obtained. p16 expression was evaluated by immunohistochemistry. The detection of HPV16/18 DNA was performed by polymerase chain reaction.  Results: Of all, 172 specimens (42.7%) were presented with amplifiable extracted DNA. Among these, 62.8% were positive for p16, 8.1% were positive for HPV16/18, and 5.8% were positive for both methods. Of all HPV-positive specimens, HPV18 was detected in 57.1%; HPV16 in 14.3%; and HPV16 and 18 (co-infection) in 28.6%. The prevalence of HPV16/18 varied between centers, with the highest rate in the northern center (20.0%). There was no significant correlation between p16 expression and HPV16/18. There were no significant associations of p16 expression and/or HPV16/18 with all variables. CONCLUSIONS: The prevalence of HPV16/18 infection in OSCC geographically varied in Thailand, with the highest rate in the northern region. Poor correlation between p16 and HPV16/18 suggests p16 not be used as a surrogate marker for HPV-positive OSCC.
.


Assuntos
Carcinoma de Células Escamosas/virologia , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Neoplasias Bucais/virologia , Infecções por Papillomavirus/complicações , Idoso , Carcinoma de Células Escamosas/epidemiologia , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Infecções por Papillomavirus/virologia , Prognóstico , Tailândia/epidemiologia
16.
Indian J Cancer ; 57(4): 481-484, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33078758

RESUMO

Worldwide, hospitals are facing problems in managing cancer patients during the ongoing COVID-19 pandemic. Given the immense cancer burden of oral cancer in India, scheduling surgeries are becoming increasingly difficult. Upfront surgeries are recommended for curative treatment of oral cancers and postponing them raises the fear of progression. Metronomic chemotherapy can be considered during the waiting period given its potential oncological benefits and ease of administration without much toxicity.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Infecções por Coronavirus/complicações , Neoplasias Bucais/tratamento farmacológico , Pandemias , Pneumonia Viral/complicações , Administração Metronômica , Protocolos de Quimioterapia Combinada Antineoplásica/provisão & distribuição , COVID-19 , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/virologia , Humanos , Índia/epidemiologia , Neoplasias Bucais/complicações , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/virologia , Procedimentos Cirúrgicos Bucais , Pneumonia Viral/epidemiologia , Pneumonia Viral/virologia
17.
Oral Oncol ; 111: 105031, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33069060

RESUMO

OBJECTIVES: Human papillomavirus infection and p16-overexpression is a principal cause and favorable prognostic factor for oropharyngeal squamous cell carcinomas but the value as prognostic marker in oral cavity squamous cell carcinomas (OSCC) is undetermined. MATERIALS AND METHODS: All patients diagnosed with OSCC in Eastern Denmark in the period 2008-2014 were enrolled. Survival estimates were evaluated as overall survival (OS) and progression free survival (PFS) by Kaplan-Meier survival curves and multivariate Cox-regression analyses. RESULTS: We included 575 patients from which 13% (n = 69) had p16-positive tumors. The 5-year OS were 55% and 62% for the p16-negative and p16-positive patients, respectively, and the 5-year PFS were 48% and 50%. In a multivariate survival analysis, p16-positivity showed no significant influence on OS (HR: 1.06 [0.67-1.70], p = 0.79) and PFS (HR: 1.11 [0.76-1.63], p = 0.58). CONCLUSION: In this population-based cohort of non-selected OSCC patients, we found no difference in survival outcomes when stratified on p16-overexpression status.


Assuntos
Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Genes p16 , Neoplasias Bucais/metabolismo , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Dinamarca , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/genética , Neoplasias Bucais/mortalidade , Neoplasias Bucais/virologia , Papillomaviridae , Prognóstico , Análise de Regressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
18.
Asian Pac J Cancer Prev ; 21(10): 3093-3097, 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33112572

RESUMO

OBJECTIVE: The infection of human papillomaviruses (HPVs) plays a role in the development of oral squamous cell carcinoma (OSCC). A poor oral hygiene and dental calculus may cause the infection to persist. Therefore, this study aimed to assess whether this dental calculus could serve as a potential biosource in early detection of HPVs in patients with OSCC. METHODS: DNA was isolated from the dental calculus of people diagnosed with OSCC, and MY09/11 primer set was used to detect the presence of HPV. The positive samples were further sequenced and aligned using megablast NCBI BLAST tool to identify the HPV genotype. RESULTS: Electrophoresis examination showed that 4 of 14 samples collected (29%) had a clear single band, of which three had 97% to 99% similarity to a high-risk genotype HPV-58. Meanwhile, the other sample had 99% similarity to an unclassified papillomaviridae. CONCLUSION: Dental calculus is a promising source of HPV in oral cavity and could be used as a biomarker for early detection.


Assuntos
Carcinoma de Células Escamosas/diagnóstico , DNA Viral/genética , Cálculos Dentários/química , Neoplasias Bucais/diagnóstico , Papillomaviridae/genética , Infecções por Papillomavirus/diagnóstico , Adulto , Idoso , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/virologia , DNA Viral/análise , Feminino , Seguimentos , Genótipo , Humanos , Indonésia/epidemiologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/epidemiologia , Neoplasias Bucais/virologia , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/virologia , Prognóstico , Adulto Jovem
19.
Anticancer Res ; 40(11): 6355-6366, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109573

RESUMO

BACKGROUND/AIM: p16 and PTEN are tumor suppressor genes. Loss of these molecules in oral squamous cell carcinoma (OSCC) has been studied worldwide. In this study, we explored whether p16 cooperates with inactive PTEN during the pathogenesis of OSCC, especially in regard to tumor aggressiveness and proliferation. MATERIALS AND METHODS: Immunocytochemistry and western blot analysis were used to examine the levels of p16 and PTEN. Sequencing analysis was performed to identify mutations in the PTEN gene and HPV infection. Fluorescence in situ hybridization was used to examine the presence of the PTEN locus. RESULTS: PTEN analysis showed high positivity in T4 samples. HPV-positive tumors correlated with tabagism, tumor size 3 and 4, disease stages 3 and 4, presence of lymph node metastasis (N1) and poor differentiation. Immunoexpression of p16 was strongly correlated with the presence of HPV. CONCLUSION: PTEN demonstrated a higher reactivity in advanced disease stages and p16 was strongly associated with HPV. Viral presence decreases tumor aggressiveness. Patients with advanced stage lesions demonstrated lower survival rate.


Assuntos
Carcinoma de Células Escamosas/genética , Inibidor p16 de Quinase Dependente de Ciclina/genética , Neoplasias Bucais/genética , PTEN Fosfo-Hidrolase/genética , Adulto , Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Hibridização in Situ Fluorescente , Perda de Heterozigosidade/genética , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/patologia , Infecções por Papillomavirus/virologia
20.
Oral Oncol ; 111: 105024, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33065374

RESUMO

OBJECTIVES: To examine the impact of treatment sequences of Immune checkpoint inhibitor (ICI) and cetuximab on clinical outcomes in patients with recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Clinicopathologic data were retrospectively collected on patients with R/M HNSCC who received ICI treatment. Association between treatment sequence and clinical outcomes were assessed. RESULTS: A total of 113 patients with R/M HNSCC were analyzed. Patients who had cetuximab prior to ICI had worse overall (HR, 1.83) and progression-free survival (HR, 1.76) compare to those without prior cetuximab. Among patients who had subsequent therapy after ICI, cetuximab-based therapy was associated with a trend toward higher response rate and longer survival than non-cetuximab regimen. CONCLUSION: Our single institution analysis showed that treatment sequence of cetuximab and ICI in R/M HNSCC may affect clinical outcomes. Cetuximab prior to ICI was associated with worse outcomes while the efficacy of cetuximab may be enhanced after ICI therapy.


Assuntos
Antineoplásicos Imunológicos/administração & dosagem , Cetuximab/administração & dosagem , Inibidores de Checkpoint Imunológico/administração & dosagem , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Esquema de Medicação , Feminino , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/mortalidade , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/virologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/mortalidade , Neoplasias Bucais/patologia , Neoplasias Bucais/virologia , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Papillomaviridae , Neoplasias dos Seios Paranasais/tratamento farmacológico , Neoplasias dos Seios Paranasais/mortalidade , Neoplasias dos Seios Paranasais/patologia , Neoplasias dos Seios Paranasais/virologia , Neoplasias Faríngeas/tratamento farmacológico , Neoplasias Faríngeas/mortalidade , Neoplasias Faríngeas/patologia , Neoplasias Faríngeas/virologia , Intervalo Livre de Progressão , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
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