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1.
Int J Mol Sci ; 22(12)2021 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-34201353

RESUMO

We identified the microRNA (miRNA) expression signature of head and neck squamous cell carcinoma (HNSCC) tissues by RNA sequencing, in which 168 miRNAs were significantly upregulated, including both strands of the miR-31 duplex (miR-31-5p and miR-31-3p). The aims of this study were to identify networks of tumor suppressor genes regulated by miR-31-5p and miR-31-3p in HNSCC cells. Our functional assays showed that inhibition of miR-31-5p and miR-31-3p attenuated cancer cell malignant phenotypes (cell proliferation, migration, and invasion), suggesting that they had oncogenic potential in HNSCC cells. Our in silico analysis revealed 146 genes regulated by miR-31 in HNSCC cells. Among these targets, the low expression of seven genes (miR-31-5p targets: CACNB2 and IL34; miR-31-3p targets: CGNL1, CNTN3, GAS7, HOPX, and PBX1) was closely associated with poor prognosis in HNSCC. According to multivariate Cox regression analyses, the expression levels of five of those genes (CACNB2: p = 0.0189; IL34: p = 0.0425; CGNL1: p = 0.0014; CNTN3: p = 0.0304; and GAS7: p = 0.0412) were independent prognostic factors in patients with HNSCC. Our miRNA signature and miRNA-based approach will provide new insights into the molecular pathogenesis of HNSCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Regulação Neoplásica da Expressão Gênica , Genes Supressores de Tumor , Neoplasias de Cabeça e Pescoço/patologia , MicroRNAs/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Biomarcadores Tumorais/genética , Proliferação de Células , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Taxa de Sobrevida , Células Tumorais Cultivadas
2.
Int J Mol Sci ; 22(12)2021 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-34204834

RESUMO

In head and neck cancers, the effectiveness of cisplatin (CisPt) treatment is limited by its toxicity, especially when higher doses are necessary, and the possible occurrence of cisplatin resistance. This study evaluated the effects of resveratrol (RSV) on the expression of different genes involved in the response of human tumor cells (FaDu, PE/CA-PJ49) to cisplatin therapy. Our results revealed that RSV induced apoptosis amplification in both FaDu and PE/CA-PJ49 cells and modulated the expression of specific genes differently than in normal HaCaT cells. In FaDu cells, combined CisPt + RSV treatment induced an increase in apoptosis, which was associated with an increase in c-MYC and TP53 and a decrease in BCL-2 expression. While CisPt + RSV treatment induced apoptosis in PE/CA-PJ49 cells by inhibition of BCL-2 associated with high levels of MDM-2 and subsequently led to inhibition of TP53 gene expression. Decreased c-MYC expression in PE/CA-PJ49 treated with CisPt + RSV was accompanied by cell cycle blockage in G0/G1 phase. In conclusion, RSV influences tumor cell response to CisPt by inducing apoptosis and modulating gene expression. In addition, in normal HaCaT cells, RSV was able to reduce the harmful effects of CisPt.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/patologia , Resveratrol/farmacologia , Apoptose/genética , Ciclo Celular/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Cisplatino/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Humanos , Concentração Inibidora 50
3.
Anticancer Res ; 41(7): 3519-3522, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230147

RESUMO

BACKGROUND/AIM: Electrochemotherapy (ECT) is a predominately palliative treatment for cutaneous metastases where an electric field is used to increase the intracellular accumulation of a chemotherapeutic drug (bleomycin or cisplatin). ECT induces a strong anti-vascular effect and endothelial cells seem especially vulnerable. To date, almost no neurological and/or cerebrovascular complications after ECT treatment have been published. In this paper two such cases are reported. CASE REPORT: A seizure in a man treated with ECT for a basal cell carcinoma in the temporal region and a fatal ischemic stroke in a woman treated for cutaneous metastases in the neck are reported. In both cases a causal relationship to ECT treatment was strongly suspected. CONCLUSION: ECT in the head and neck can potentially cause severe neurological complications. Ultrasound is recommended for ECT treatment in the neck.


Assuntos
Carcinoma Basocelular/tratamento farmacológico , Eletroquimioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Cabeça/patologia , Pescoço/patologia , Doenças do Sistema Nervoso/induzido quimicamente , Neoplasias Cutâneas/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Carcinoma Basocelular/patologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/patologia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Doenças do Sistema Nervoso/patologia , Neoplasias Cutâneas/patologia
4.
Anticancer Res ; 41(6): 2773-2779, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083267

RESUMO

Head and neck carcinoma (HNC) comprises a variety of pathological entities. Among them, squamous cell carcinoma (SCC) is histo-pathologically prominent. Specific malignancies, such as nasopharyngeal carcinoma (NPC) arise also from the same anatomical region. In all of them, genomic instability (GI) is implicated not only in the early stages of epithelial malignant transformation, but also in the aggressiveness of the corresponding phenotypes. Among the molecules that are frequently deregulated in solid malignancies including HNCs, topoisomerases (Topo) are of increased significance due to their involvement in DNA topological, structural, and functional stability. The main members are Topo I (20q11), Topo II alpha (17q21) and Topo IIb (3p24). In the current article, we describe the mechanisms of Topo I and Topo IIa deregulation leading to GI in a variety of HNCs. Furthermore, novel data regarding the corresponding targeted therapeutic strategies are presented.


Assuntos
DNA Topoisomerases Tipo I/metabolismo , Instabilidade Genômica , Neoplasias de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/enzimologia , DNA Topoisomerases Tipo I/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
5.
Anticancer Res ; 41(6): 3055-3058, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083297

RESUMO

BACKGROUND/AIM: Patients with advanced squamous cell carcinoma of the head-and-neck (SCCHN) may be assigned to palliative irradiation. A survival score was developed for this group to support treatment personalization. PATIENTS AND METHODS: Seventy-eight patients who received palliative irradiation for SCCHN and had complete data regarding performance score, pre-radiotherapy hemoglobin levels, and main tumor site were included in this retrospective study. Six-month survival rates of these factors were divided by 10 (factor scores) and added for each patient (total patient scores). RESULTS: Total patient scores ranged between 8 and 15 points. Three groups were designed based on the 6-month survival rates, namely 8-9 (n=15), 11-13 (n=36), and 14-15 (n=27) points. Six-month survival rates were 13%, 28%, and 63%, and median survival times were 1, 2, and 11 months (p=0.001). CONCLUSION: A new survival score including three prognostic groups was developed. This new tool can help physicians when designing personalized treatments for patients with SCCHN scheduled for palliative irradiation.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Cuidados Paliativos , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Taxa de Sobrevida , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Medicina de Precisão , Prognóstico , Dosagem Radioterapêutica , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
6.
Anticancer Res ; 41(6): 3205-3210, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34083316

RESUMO

BACKGROUND/AIM: A considerable number of patients with advanced head-and-neck cancer (SCCHN) receive palliative radiotherapy. This study aimed to identify prognostic factors for survival to facilitate personalized treatment for these patients. PATIENTS AND METHODS: Ninety-two patients receiving palliative radiotherapy for SCCHN were retrospectively analyzed. Fourteen characteristics were evaluated for survival including age, gender, performance score, pre-radiotherapy hemoglobin, tumor site and stage, histologic grade, p16-status, equivalent dose in 2 Gy-fractions (EQD2), completion of radiotherapy, upfront surgery and systemic therapy. RESULTS: On univariate analysis, improved survival was significantly associated with pre-radiotherapy hemoglobin ≥12 g/dl (p=0.003), EQD2 >42.3 Gy (p=0.003) and completion of radiotherapy (p<0.001). In the multivariate analysis, hemoglobin levels remained significant (p=0.024). Trends were found for EQD2 (p=0.057) and completion of radiotherapy (p=0.093). CONCLUSION: Prognostic factors for survival were identified that can facilitate treatment personalization. The fact that higher EQD2 and completion of radiotherapy were associated with improved survival demonstrates the importance of close monitoring and care of these patients during radiotherapy.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Cuidados Paliativos , Radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Humanos , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
7.
Nat Commun ; 12(1): 3349, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099645

RESUMO

Current immunotherapy paradigms aim to reinvigorate CD8+ T cells, but the contribution of humoral immunity to antitumor immunity remains understudied. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC) caused by human papillomavirus infection (HPV+), patients have transcriptional signatures of germinal center (GC) tumor infiltrating B cells (TIL-Bs) and spatial organization of immune cells consistent with tertiary lymphoid structures (TLS) with GCs, both of which correlate with favorable outcome. GC TIL-Bs in HPV+ HNSCC are characterized by distinct waves of gene expression consistent with dark zone, light zone and a transitional state of GC B cells. Semaphorin 4a expression is enhanced on GC TIL-Bs present in TLS of HPV+ HNSCC and during the differentiation of TIL-Bs. Our study suggests that therapeutics to enhance TIL-B responses in HNSCC should be prioritized in future studies to determine if they can complement current T cell mediated immunotherapies.


Assuntos
Linfócitos B/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Estruturas Linfoides Terciárias/metabolismo , Análise de Variância , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos/imunologia , Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imunoterapia/métodos , Infecções por Papillomavirus , Semaforinas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Análise de Sobrevida , Linfócitos T
8.
Nat Commun ; 12(1): 3974, 2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34172737

RESUMO

Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). Although significant progress has been made in understanding the self-renewal and pro-tumorigenic potentials of CSCs, a key challenge remains on how to eliminate CSCs and halt metastasis effectively. Here we show that super-enhancers (SEs) play a critical role in the transcription of cancer stemness genes as well as pro-metastatic genes, thereby controlling their tumorigenic potential and metastasis. Mechanistically, we find that bromodomain-containing protein 4 (BRD4) recruits Mediators and NF-κB p65 to form SEs at cancer stemness genes such as TP63, MET and FOSL1, in addition to oncogenic transcripts. In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. Moreover, disrupting SEs also inhibits the invasive growth and lymph node metastasis of human CSCs isolated from human HNSCC. Taken together, our results suggest that targeting SEs may serve as an effective therapy for HNSCC by eliminating CSCs.


Assuntos
Elementos Facilitadores Genéticos , Neoplasias de Cabeça e Pescoço/patologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Antineoplásicos/farmacologia , Azepinas/farmacologia , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Humanos , Metástase Linfática/tratamento farmacológico , Metástase Linfática/prevenção & controle , Subunidade 1 do Complexo Mediador/genética , Subunidade 1 do Complexo Mediador/metabolismo , Camundongos Endogâmicos C57BL , Camundongos SCID , NF-kappa B/genética , Células-Tronco Neoplásicas/patologia , Complexo Repressor Polycomb 1/antagonistas & inibidores , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Triazóis/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Life Sci ; 279: 119709, 2021 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-34102188

RESUMO

Head and Neck tumors are metabolically highly altered solid tumors. Head and Neck cancer cells may utilise different metabolic pathways for energy production. Whereas, glycolysis is the major source coupled with oxidative phosphorylation in a metabolic symbiosis manner that results in the proliferation and metastasis in Head and Neck Cancer. The monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1-4 are responsible for transporting monocarboxylates such as l-lactate and pyruvate, and ketone bodies across the plasma membrane. Additionally, MCTs mediate absorption and distribution of monocarboxylates across the cell membrane. Head and Neck cancer cells are highly glycolytic in nature and generate significant amount of lactic acid in the extracellular environment. In such condition, MCTs play a critical role in the regulation of pH, and lactate shuttle maintenance. The intracellular lactate accumulation is harmful for the cells since it drastically lowers the intracellular pH. MCTs facilitate the export of lactate out of the cell. The lactate export mediated by MCTs is crucial for the cancer cells survival. Therefore, targeting MCTs is important and could be a potential therapeutic approach to control growth of the tumor.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Redes e Vias Metabólicas , Transportadores de Ácidos Monocarboxílicos/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Transporte Biológico , Glicólise , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Fosforilação Oxidativa , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo
10.
Int J Mol Sci ; 22(9)2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-34067112

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous disease arising from the mucosa of the upper aerodigestive tract. Despite multimodality treatments approximately half of all patients with locally advanced disease relapse and the prognosis of patients with recurrent or metastatic HNSCC is dismal. The introduction of checkpoint inhibitors improved the treatment options for these patients and pembrolizumab alone or in combination with a platinum and fluorouracil is now the standard of care for first-line therapy. However, approximately only one third of unselected patients respond to this combination and the response rate to checkpoint inhibitors alone is even lower. This shows that there is an urgent need to improve prognostication and prediction of treatment benefits in patients with HNSCC. In this review, we summarize the most relevant risk factors in the field and discuss their roles and limitations. The human papilloma virus (HPV) status for patients with oropharyngeal cancer and the combined positive score are the only biomarkers consistently used in clinical routine. Other factors, such as the tumor mutational burden and the immune microenvironment have been highly studied and are promising but need validation in prospective trials.


Assuntos
Neoplasias de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Antígeno B7-H1/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Mutação/genética , Estadiamento de Neoplasias , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Tabaco
11.
DNA Cell Biol ; 40(6): 720-732, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33979530

RESUMO

Many kinds of cancer cells are intrinsically sensitive to ferroptosis, and research interest regarding ferroptosis has been sparked by its significant role in many detrimental diseases. Ferroptosis is a novel type of iron-dependent cell death mediated by accumulation of reactive oxygen species and lipid peroxidation. Furthermore, a large number of small agents can induce ferroptosis in numerous kinds of cancer cells, including prostate cancer, pancreatic cancer, breast cancer, lymphomas, and renal cancer. These insights may help discover novel approaches for cancer therapeutic strategies; however, there is considerable uncertainty regarding ferroptosis in head and neck cancer (HNC). So far, no review of the current studies on this topic has been published. Therefore, we here elaborate the mechanisms of ferroptosis and summarize the latest findings regarding its role in HNC according to current literature. The respective findings shed light on the role of ferroptosis in HNC treatment with a number of important implications for future practice in HNC management, as outlined in this review.


Assuntos
Ferroptose , Neoplasias de Cabeça e Pescoço , Carcinoma de Células Escamosas de Cabeça e Pescoço , Biomarcadores Tumorais/metabolismo , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia
12.
Cancer Causes Control ; 32(8): 883-894, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34003396

RESUMO

INTRODUCTION: Esophageal cancer (EC) is an aggressive malignancy with poor prognosis. Mortality and disease stage at diagnosis are important indicators of improvements in cancer prevention and control. We examined United States trends in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC) mortality and stage at diagnosis by race and ethnicity. METHODS: We used Surveillance, Epidemiology, and End Results (SEER) data to identify individuals with histologically confirmed EAC and ESCC between 1 January 1992 and 31 December 2016. For both EAC and ESCC, we calculated age-adjusted mortality and the proportion presenting at each stage by race/ethnicity, sex, and year. We then calculated the annual percent change (APC) in each indicator by race/ethnicity and examined changes over time. RESULTS: The study included 19,257 EAC cases and 15,162 ESCC cases. EAC mortality increased significantly overall and in non-Hispanic Whites from 1993 to 2012 and from 1993 to 2010, respectively. EAC mortality continued to rise among non-Hispanic Blacks (NHB) (APC = 1.60, p = 0.01). NHB experienced the fastest decline in ESCC mortality (APC = - 4.53, p < 0.001) yet maintained the highest mortality at the end of the study period. Proportions of late stage disease increased overall by 18.5 and 24.5 percentage points for EAC and ESCC respectively; trends varied by race/ethnicity. CONCLUSION: We found notable differences in trends in EAC and ESCC mortality and stage at diagnosis by race/ethnicity. Stage migration resulting from improvements in diagnosis and treatment may partially explain recent trends in disease stage at diagnosis. Future efforts should identify factors driving current esophageal cancer disparities.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas do Esôfago/patologia , Adulto , Grupos Étnicos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Incidência , Masculino , Estados Unidos
13.
Aging (Albany NY) ; 13(9): 13048-13060, 2021 05 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962400

RESUMO

Epithelial-mesenchymal transition (EMT) is closely correlated to metastasis formation generation and maintenance of cancer stem cells, nevertheless, the underlying mechanisms are unclear. The aim of this study is to investigate the role of maternal embryonic leucine-zipper kinase (MELK) in EMT regulation in oral squamous cell carcinoma (OSCC). We found that there was overexpression of MELK in human OSCC tissues, and high MELK expression was correlated with lymphatic metastasis and led to poor prognosis in patients with OSCC. We also confirmed that MELK is closely correlated to the EMT process using a human OSCC tissue microarray. Additionally, MELK expression was observed to be regulated in several OSCC cell lines, and knockdown of MELK genes inhibited cell proliferation, migration, invasion and EMT of OSCC cells in vitro. Furthermore, silencing of MELK suppressed tumour growth in vivo, and experimental research verified that MELK may augment OSCC development via mediating the Wnt/Notch signalling pathway. Our findings suggest that MELK serves as an oncogene to improve malignant development of OSCC via enhancing EMT, and MELK might be a potential target for anticancer therapeutic.


Assuntos
Movimento Celular/fisiologia , Metástase Linfática/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas/genética , Proliferação de Células/fisiologia , Expressão Ectópica do Gene/fisiologia , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Neoplasias Bucais/metabolismo , Células-Tronco Neoplásicas/metabolismo
14.
Cancer Med ; 10(10): 3231-3239, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33934525

RESUMO

BACKGROUND: Only high-risk tumors with extranodal extension (ENE) and/or positive surgical margins (PSM) benefit from adjuvant therapy (AT) with concurrent chemoradiation (CRT) compared to radiation therapy (RT) in locally advanced head and neck squamous cell carcinoma (HNSCC). Optimal treatment for intermediate-risk tumors remains controversial. We categorized patients based on their surgical pathologic risk factors and described AT treatment patterns and associated survival outcomes. METHODS: Patients were identified from CHANCE, a population-based study, and risk was classified based on surgical pathology review. High-risk patients (n = 204) required ENE and/or PSM. Intermediate-risk (n = 186) patients had pathological T3/T4 disease, perineural invasion (PNI), lymphovascular invasion (LVI), or positive lymph nodes without ENE. Low-risk patients (n = 226) had none of these features. RESULTS: We identified 616 HPV-negative HNSCC patients who received primary surgical resection with neck dissection. High-risk patients receiving AT had favorable OS (HR 0.50, p = 0.013) which was significantly improved with the addition of chemotherapy compared to RT alone (HR 0.47, p = 0.021). When stratified by node status, the survival benefit of AT in high-risk patients persisted only among those who were node-positive (HR: 0.17, p < 0.0005). On the contrary, intermediate-risk patients did not benefit from AT (HR: 1.26, p = 0.380) and the addition of chemotherapy was associated with significantly worse OS compared to RT (HR: 1.76, p = 0.046). CONCLUSION: In high-risk patients, adjuvant chemoradiotherapy improved OS compared to RT alone. The greatest benefit was in node-positive cases. In intermediate-risk patients, the addition of chemotherapy to RT increased mortality risk and therefore should only be used cautiously in these patients.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Idoso , Quimiorradioterapia Adjuvante/métodos , Terapia Combinada/métodos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Linfonodos/patologia , Masculino , Margens de Excisão , Pessoa de Meia-Idade , Esvaziamento Cervical/métodos , Estadiamento de Neoplasias/métodos , Infecções por Papillomavirus/patologia , Radioterapia Adjuvante/métodos , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
15.
Int J Mol Sci ; 22(9)2021 Apr 25.
Artigo em Inglês | MEDLINE | ID: mdl-33922946

RESUMO

Locoregional recurrence is a major reason for therapy failure after surgical resection of head and neck squamous cell carcinoma (HNSCC). The physiological process of postoperative wound healing could potentially support the proliferation of remaining tumor cells. The aim of this study was to evaluate the influence of wound fluid (WF) on the cell cycle distribution and a potential induction of epithelial-mesenchymal transition (EMT). To verify this hypothesis, we incubated FaDu and HLaC78 cells with postoperative WF from patients after neck dissection. Cell viability in dependence of WF concentration and cisplatin was measured by flow cytometry. Cell cycle analysis was performed by flow cytometry and EMT-marker expression by rtPCR. WF showed high concentrations of interleukin (IL)-6, IL-8, IL-10, CCL2, MCP-1, EGF, angiogenin, and leptin. The cultivation of tumor cells with WF resulted in a significant increase in cell proliferation without affecting the cell cycle. In addition, there was a significant enhancement of the mesenchymal markers Snail 2 and vimentin, while the expression of the epithelial marker E-cadherin was significantly decreased. After cisplatin treatment, tumor cells incubated with WF showed a significantly higher resistance compared with the control group. The effect of cisplatin-resistance was dependent on the WF concentration. In summary, proinflammatory cytokines are predominantly found in WF. Furthermore, the results suggest that EMT can be induced by WF, which could be a possible mechanism for cisplatin resistance.


Assuntos
Cisplatino/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Ferimentos e Lesões/patologia , Idoso , Idoso de 80 Anos ou mais , Líquidos Corporais/fisiologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Resistencia a Medicamentos Antineoplásicos/fisiologia , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
16.
J Cancer Res Clin Oncol ; 147(7): 1905-1916, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33791846

RESUMO

PURPOSE: The clinical outcome of head and neck squamous cell carcinoma (HNSCC) remains poor, partly due to the presence of resistant cancer stem cells (CSCs) which are responsible of recurrences. CSCs have low EGFR expression and, conversely, overexpress the anti-apoptotic Bcl-2 protein, which is involved in resistance to apoptosis and the invasion/migration capacities of tumour cells. METHODS: The combination therapy of ABT-199, a Bcl-2 inhibitor, cetuximab an EGFR inhibitor, and radiation using an HNSCC model (SQ20B cell line) and its corresponding CSC subpopulation were evaluated in vitro (2D/3D cell proliferation; invasion/migration and apoptosis using videomicroscopy) and in vivo. RESULTS: Cetuximab strongly inhibited 2D and 3D cell proliferation, as well as invasion/migration, only in non-CSC-SQ20B cells, whereas ABT-199 selectively inhibited these mechanisms in SQ20B/CSCs. The combination of irradiation + cetuximab + ABT-199 increased the inhibition of the 2D and 3D cell proliferation, invasion/migration, and resistance to apoptosis in both cell sub-populations. In addition, in a nude mouse model with heterotopic tumour xenograft, a treatment combining cetuximab + ABT-199 with fractional irradiation strongly delayed the tumour growth and increased in vivo lifespan without side effects. CONCLUSION: Based on the present results, this triple combination therapy may represent a new opportunity for testing in clinical trials, particularly in locally advanced HNSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Quimiorradioterapia/métodos , Neoplasias de Cabeça e Pescoço/terapia , Células-Tronco Neoplásicas/patologia , Proteínas Proto-Oncogênicas c-bcl-2/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Animais , Apoptose , Compostos Bicíclicos Heterocíclicos com Pontes/administração & dosagem , Movimento Celular , Proliferação de Células , Cetuximab/administração & dosagem , Receptores ErbB/antagonistas & inibidores , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/efeitos da radiação , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Sulfonamidas/administração & dosagem , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cancer Treat Rev ; 97: 102192, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33819755

RESUMO

Anti-programmed cell death protein 1 immunotherapy has become the new standard in the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, the population that benefits is small, warranting drug combinations and novel approaches. HNSCC is a profoundly immunosuppressive disease, characterized by the interplay among different immune regulatory pathways. As clinical trials evaluating immunotherapy combinations in patients with HNSCC have started producing preliminary results, preclinical evidence on potential new targets for combination immunotherapy continues to accumulate. This review summarizes emerging clinical and preclinical data on immunotherapy combinations for the treatment of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Quimioterapia Combinada , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
18.
J Med Chem ; 64(8): 4787-4809, 2021 04 22.
Artigo em Inglês | MEDLINE | ID: mdl-33822622

RESUMO

To investigate the importance of the chirality and precise structure at position 3(1') of pyropheophorbide-a for tumor cell specificity and photodynamic therapy (PDT), a series of photosensitizers (PSs) was synthesized: (a) with and without chirality at position 3(1'), (b) alkyl ether chain with a variable number of chiral centers, (c) hexyl ether versus thioether side chain, and (d) methyl ester versus carboxylic acid group at position 172. The cellular uptake and specificity were defined in human lung and head/neck cancer cells. PSs without a chiral center and with an alkyl chain or thioether functionalities showed limited uptake and PDT efficacy. Replacing the methyl group at the chiral center with a propyl group or introducing an additional chiral center improved cellular retention and tumor cell specificity. Replacing the carboxylic acid with methyl ester at position 172 lowered cellular uptake and PDT efficacy. A direct correlation between the PS uptake in vitro and in vivo was identified.


Assuntos
Clorofila/análogos & derivados , Fármacos Fotossensibilizantes/metabolismo , Animais , Clorofila/química , Clorofila/metabolismo , Clorofila/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Luz , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Camundongos , Camundongos SCID , Microscopia de Fluorescência , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Solubilidade , Estereoisomerismo , Transplante Heterólogo , Células Tumorais Cultivadas
19.
BMC Cancer ; 21(1): 420, 2021 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-33863315

RESUMO

BACKGROUND: Previous studies reported cutaneous melanoma in head and neck (HNM) differed from those in other regions (body melanoma, BM). Individualized tools to predict the survival of patients with HNM or BM remain insufficient. We aimed at comparing the characteristics of HNM and BM, developing and validating nomograms for predicting the survival of patients with HNM or BM. METHODS: The information of patients with HNM or BM from 2004 to 2015 was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. The HNM group and BM group were randomly divided into training and validation cohorts. We used the Kaplan-Meier method and multivariate Cox models to identify independent prognostic factors. Nomograms were developed via the rms and dynnom packages, and were measured by the concordance index (C-index), the area under the curve (AUC) of the receiver operating characteristic (ROC) curve and calibration plots. RESULTS: Of 70,605 patients acquired, 21% had HNM and 79% had BM. The HNM group contained more older patients, male sex and lentigo maligna melanoma, and more frequently had thicker tumors and metastases than the BM group. The 5-year cancer-specific survival (CSS) and overall survival (OS) rates were 88.1 ± 0.3% and 74.4 ± 0.4% in the HNM group and 92.5 ± 0.1% and 85.8 ± 0.2% in the BM group, respectively. Eight variables (age, sex, histology, thickness, ulceration, stage, metastases, and surgery) were identified to construct nomograms of CSS and OS for patients with HNM or BM. Additionally, four dynamic nomograms were available on web. The internal and external validation of each nomogram showed high C-index values (0.785-0.896) and AUC values (0.81-0.925), and the calibration plots showed great consistency. CONCLUSIONS: The characteristics of HNM and BM are heterogeneous. We constructed and validated four nomograms for predicting the 3-, 5- and 10-year CSS and OS probabilities of patients with HNM or BM. These nomograms can serve as practical clinical tools for survival prediction and individual health management.


Assuntos
Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Melanoma/mortalidade , Melanoma/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Área Sob a Curva , Feminino , Neoplasias de Cabeça e Pescoço/epidemiologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Melanoma/epidemiologia , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Nomogramas , Especificidade de Órgãos , Vigilância da População , Prognóstico , Modelos de Riscos Proporcionais , Curva ROC , Reprodutibilidade dos Testes , Programa de SEER
20.
Anticancer Res ; 41(4): 2045-2051, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33813412

RESUMO

BACKGROUND/AIM: To retrospectively evaluate the efficacy and safety of modified TPEx (docetaxel 60 mg/m2 on day 1, cisplatin 60 mg/m2 on day 1, and weekly cetuximab 250 mg/m2 with loading dose of 400 mg/m2) followed by maintenance cetuximab as first-line treatment for inoperable recurrent and/or metastatic squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: We analyzed 22 Japanese patients receiving modified TPEx every 21 days for four cycles with or without prophylactic granulocyte colony-stimulating factor (G-CSF). RESULTS: The best overall response rate was 55% [95% confidence interval (CI)=35-73]. The median progression-free survival and overall survival were 8.9 months (95%CI=3.9-10.2) and 14.3 months (95%CI=10.1-28.2), respectively. Without prophylactic G-CSF, Grade 3/4 neutropenia and febrile neutropenia was common (94% versus 20%; p=0.003 and 41% versus 0%; p=0.11, respectively). CONCLUSION: The modified TPEx is effective, while prophylactic G-CSF is essential.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Docetaxel/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Adulto , Idoso , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Cetuximab/efeitos adversos , Cisplatino/efeitos adversos , Docetaxel/efeitos adversos , Esquema de Medicação , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Resultado do Tratamento
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