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1.
Med Oncol ; 36(11): 93, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31595355

RESUMO

In patients with locally advanced human papillomavirus (HPV)-unrelated head and neck squamous-cell carcinoma (HNSCC), cisplatin and radiation therapy (CisRT) resulted in a local-regional recurrence (LRR) rate of 35%, progression-free survival (PFS) of 49%, and overall survival (OS) of 60%. We, and others, showed that nab-paclitaxel is an active agent in metastatic and locally advanced HNSCC. The aim of this report was to assess the efficacy of nab-paclitaxel-based induction chemotherapy and CisRT in HPV-unrelated HNSCC. We performed a retrospective single-institution analysis of patients treated with nab-paclitaxel-based chemotherapy and CisRT. Key inclusion criteria included stage III-IV HPV-unrelated HNSCC. Induction chemotherapy included nab-paclitaxel and cisplatin (AP), AP + 5-fluorouracil (APF), or APF + Cetuximab (APF-C). Endpoints included LRR, overall relapse, PFS, and OS. Thirty-eight patients were the subject of this analysis. Patient characteristics included median age 59 years (IQR: 54-64) and smoking history in 36 patients (95%). Primary tumor sites included larynx/hypopharynx (27), p16 negative oropharynx (10), and oral cavity (1). Most patients had bulky disease: 82% T3-4 (n = 31) and 74% N2b-3 (n = 28). Median follow-up was 44 months (IQR: 23-59). The three-year LRR rate was 16% (95% confidence interval [CI] 7-34) and the overall relapse rate was 22% (95% CI 11-41). The three-year PFS was 64% (95% CI 46-77) and OS was 72% (95% CI 54-84). Among patients with HPV-unrelated HNSCC, nab-paclitaxel-based induction chemotherapy and CisRT resulted in a lower-than-expected rate of LRR and more favorable PFS and OS compared to historical results with CisRT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cisplatino/uso terapêutico , 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 , Adulto , Idoso , Albuminas/administração & dosagem , Quimiorradioterapia , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Quimioterapia de Indução , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/patologia , Paclitaxel/administração & dosagem , Infecções por Papillomavirus/patologia , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
2.
Cancer Radiother ; 23(6-7): 496-499, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31471251

RESUMO

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.


Assuntos
Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias/radioterapia , Radiocirurgia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Terapia Combinada/métodos , Previsões , França , Humanos , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
3.
Gene ; 714: 143997, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31348981

RESUMO

Based on Akt1 and Jak1 key roles in apoptosis and proliferation of many cancers, the aim of this study was to find a new gene therapy strategy by silencing of these main anti-apoptotic genes for HNSCC treatment. Cancerous HN5 and normal HUVEC cell lines were treated with Akt1 and Jak1 siRNAs alone or with each other combined with/without cisplatin. The MTS, flow cytometry, 4',6-diamidino-2-phenylindole staining, real-time PCR and ELISA methods were utilized in this study. The highest percentage of apoptosis was observed in the treatment of Jak1 siRNA/cisplatin group in cancerous HN5 cells (96.5%) where this treatment showed 12.84% apoptosis in normal HUVEC cell line. Cell viability reduced significantly to 64.57% after treatment with Akt1 siRNA in HN5 treated group. Knocking down Akt1 and Jak1 genes using siRNAs could increase levels of apoptosis and reduce proliferation rate in HNSCC indicating the powerful effects of these genes siRNAs with or without chemotherapeutic agents in HNSCC treatment. In conclusion, the combination of siRNA-mediated gene-silencing strategy can be considered as a valuable and safe approach for sensitizing cancer cells to chemotherapeutic agents thus proposed further studies regarding this issue to approve some siRNA based therapeutics for using in clinic.


Assuntos
Apoptose/genética , Proliferação de Células/genética , Neoplasias de Cabeça e Pescoço/genética , Janus Quinase 1/genética , Proteínas Proto-Oncogênicas c-akt/genética , RNA Interferente Pequeno/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Apoptose/efeitos dos fármacos , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Cisplatino/farmacologia , Técnicas de Silenciamento de Genes/métodos , Inativação Gênica/efeitos dos fármacos , Inativação Gênica/fisiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Células Endoteliais da Veia Umbilical Humana , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico
4.
Toxicol Lett ; 314: 142-152, 2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31319114

RESUMO

Cadmium (Cd), an established carcinogen, is a risk factor for oral squamous cell carcinoma (OSCC). Macroautophagy/autophagy is proposed to play a pivotal role in Cd-mediated carcinogenic activity. However, the mechanisms underlying Cd-induced autophagy are poorly understood. In the present study, a CAL27 OSCC cell line exposed to 10-6 M Cd for 8 weeks was used as a model system. Repeated Cd exposure induced significant migration and invasion of CAL27 cells. Furthermore, we showed that Cd increased the autophagic flux in CAL27 cells, as evidenced by the upregulation of LC3-II and the downregulation of P62/SQSTM1. The genetic blocking of autophagy inhibited Cd-induced migration and invasion, indicating a carcinogenic role of autophagy in Cd-treated CAL27 cells. Cd-induced NUPR1 expression, which contributes to lysosomal biogenesis and expression of autophagy-related gene, was found to mechanistically initiate autophagy in CAL27 cells. Of note, NUPR1 shRNA abolished Cd-induced autophagy both in vitro and in vivo. We also found that Cd triggered the generation of MDA in a xenograft tumour model and that N-acetyl-l-cysteine, a reactive oxygen species (ROS) scavenger, abrogated the effects of Cd on NUPR1-dependent autophagy in vivo. Taken together, these results demonstrate that ROS-dependent NUPR1-mediated autophagy plays an important role in repeated Cd exposure -induced cell growth, migration and invasion in OSCC cells.


Assuntos
Acetilcisteína/farmacologia , Antioxidantes/farmacologia , Autofagia/efeitos dos fármacos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Cloreto de Cádmio/toxicidade , Movimento Celular/efeitos dos fármacos , Neoplasias Bucais/tratamento farmacológico , Proteínas de Neoplasias/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Espécies Reativas de Oxigênio/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Proteína 5 Relacionada à Autofagia/genética , Proteína 5 Relacionada à Autofagia/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Camundongos Nus , Proteínas Associadas aos Microtúbulos/metabolismo , Neoplasias Bucais/genética , Neoplasias Bucais/metabolismo , Neoplasias Bucais/patologia , Invasividade Neoplásica , Proteínas de Neoplasias/genética , Proteína Sequestossoma-1/metabolismo , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Anticancer Res ; 39(7): 3499-3506, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262874

RESUMO

BACKGROUND/AIM: The present study aimed to investigate the apoptotic effects of phenformin, a therapeutic agent for diabetes, on head and neck squamous cell carcinoma (HNSCC). MATERIALS AND METHODS: Cytotoxicity was measured by the MTT and live/dead cell assay. Phenformin-induced apoptotic FaDu cell death and its associated cellular signaling pathways were investigated by hematoxylin and eosin staining, 4',6-diamidino-2-phenylindole staining, caspase-3 activity assay, fluorescence-activated cell sorting analysis, and western blotting. RESULTS: Phenformin promoted death of and apoptotic processes in FaDu cells, including morphological alterations and nuclear condensation. Furthermore, treatment with phenformin increased caspase-3 activity and apoptotic populations via the caspase cascade through cleavage of capspase-8, -9, and -3 and poly(ADP-ribose) polymerase in FaDu cells. Moreover, phosphorylation levels of mitogen-activated protein kinases, nuclear factor-κB, and AKT were down-regulated in FaDu cells by phenformin. CONCLUSION: Phenformin induced death of FaDu cells via caspase-dependent extrinsic and intrinsic apoptosis pathways and is a promising novel therapeutic agent for HNSCC.


Assuntos
Antineoplásicos/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fenformin/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Proteína Ligante Fas/metabolismo , Humanos
6.
Anticancer Res ; 39(7): 3633-3639, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31262889

RESUMO

BACKGROUND/AIM: The aim of this study was to analyze the effect of DL-methadone on enhancing the action of the chemotherapeutic drugs cisplatin, doxorubicin, 5-fluoruracil (5-FU) and paclitaxel on head and neck squamous carcinoma (HNSCC) cell lines. MATERIALS AND METHODS: The chemotherapeutic drugs were applied alone or in combination with DL-methadone and cytotoxicity was analyzed by XTT assays. Expression of the µ-opioid receptor and the drug transporter p-glycoprotein were analyzed by qRT-PCR. RESULTS: The effect of DL-methadone strongly depended on the respective chemotherapeutic agent. The basic expression of the µ-opioid receptor was not associated with the effect of DL-methadone, rather its induction by chemotherapeutic drugs. Expression or expression induction of p-glycoprotein was higher in weak-responder cell lines. CONCLUSION: Enhancement of the toxicity of chemotherapeutic drugs by DL-methadone depends on the drug and on the cell line used.


Assuntos
Antineoplásicos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metadona/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Subfamília B de Transportador de Cassetes de Ligação de ATP/genética , Linhagem Celular Tumoral , Cisplatino/farmacologia , Doxorrubicina/farmacologia , Fluoruracila/farmacologia , Neoplasias de Cabeça e Pescoço/genética , Humanos , Paclitaxel/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética
7.
Med Oncol ; 36(8): 68, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31190132

RESUMO

This study was designed to evaluate the objective response after hypofractionated radiotherapy (HFRT) combined with cetuximab (HFBRT) in vulnerable elderly patients with locally advanced head and neck squamous cell carcinoma (HNSCC). Vulnerable elderly patients with histologically proven HNSCC received HFRT (total dose 60 Gy, 3 Gy/fraction) with concurrent cetuximab (250 mg/m2 with a loading dose of 400 mg/m2 1 week before HFRT). Elderly patients were categorized as vulnerable based on mini-cog test and adult comorbidity evaluation-27 score. All patients completed the programmed HFRT and two patients received the planned cetuximab infusion. Severe acute toxicity, observed in four patients, was gastrointestinal (oral mucositis in four cases; nausea/vomiting in one case) and dermatological (acneiform eruption in three cases; radiation dermatitis in one case). Three serious adverse events were recorded in three out of six patients Overall, three patients had a partial response and three patients had progression disease 3 months after the end of the treatment. No complete response was observed. HFBRT seems to be not a safer alternative approach for vulnerable elderly patients with locally advanced HNSCC. Further prospective trials are needed to define better tumor control with less incidence of toxic effects in vulnerable elderly HNSCC patients.


Assuntos
Cetuximab/uso terapêutico , 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 , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/uso terapêutico , Quimiorradioterapia , Fracionamento da Dose de Radiação , Feminino , Humanos , Masculino , Projetos Piloto
8.
Anticancer Res ; 39(6): 3059-3065, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177149

RESUMO

BACKGROUND: Induction chemotherapy (IC) for head and neck cancer (HNC) often causes severe side-effects. However, it has still been challenging to predict the adverse events. The present study aimed to evaluate the role of hematological inflammatory markers in predicting severe side-effects caused by IC. MATERIALS AND METHODS: A total of 54 HNC patients who underwent IC were enrolled. The association between severe side-effects and pre-treatment hematological inflammatory markers [the C-reactive protein (CRP) to albumin ratio (CAR), the modified Glasgow Prognostic Score (mGPS), the neutrophil-to-lymphocyte ratio (NLR), and the platelet-to-lymphocyte ratio (PLR)] were evaluated. RESULTS: In the univariate analysis, the incidence of whole severe side-effects (grade 4), febrile neutropenia (above grade 3), and hyponatremia (above grade 3) were significantly higher in the high CAR and high GPS groups. Multivariate analysis revealed that high CAR and mGPS were independent predictors of these side-effects. CONCLUSION: CAR and mGPS were significant predictors of severe side-effects. These data can potentially offer patients an improved quality of life during cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neutropenia Febril Induzida por Quimioterapia/epidemiologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Quimioterapia de Indução/efeitos adversos , Mediadores da Inflamação/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Neutropenia Febril Induzida por Quimioterapia/sangue , Neutropenia Febril Induzida por Quimioterapia/diagnóstico , Cisplatino/efeitos adversos , Docetaxel/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/diagnóstico , Humanos , Hiponatremia/sangue , Hiponatremia/diagnóstico , Hiponatremia/epidemiologia , Incidência , Japão/epidemiologia , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Estado Nutricional , Contagem de Plaquetas , Valor Preditivo dos Testes , Estudos Retrospectivos , Fatores de Risco , Albumina Sérica Humana/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico , Fatores de Tempo , Resultado do Tratamento
9.
Phytother Res ; 33(5): 1551-1561, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31066474

RESUMO

Aacacetin, a plant flavone has shown antitumor efficacy recently. However, its associated mechanisms are poorly known. We hypothesized that the muscarinic M3 receptor (M3 R), which is highly expressed in some cancer tissue, is related to the antitumor effect of acacetin in head and neck squamous cell carcinoma (HNSCC) cells. Our results showed that 12.5- to 200-µM acacetin inhibited cell viability in dose- and time-dependent manners in HNSCC cells, but a relative higher concentration was needed for oral adenoid cystic carcinoma cells. M3 R expression level was higher in HNSCC cells than that in adenoid cystic carcinoma cells. Flow cytometry and electron microscopy confirmed acacetin-induced cell apoptosis in 22B cells, a HNSCC cell line. Acacetin promoted mitochondrial cytochrome c release and caspase 9, 3 processing. Knocking down of M3 R expression by specific siRNA significantly prevented the acacetin-induced cell viability damage, cell apoptosis, and caspase 3 activation. Besides, M3 R was also involved in acacetin-induced elevation of reactive oxygen species and intracellular calcium ([Ca2+ ]i ). These data indicate that acacetin-induced cell apoptosis in HNSCC cells may through M3 R related calcium signaling and caspase 3 activation. Acacetin is a potent natural antitumor reagent especially for the tumor cells, which highly expressed M3 R.


Assuntos
Flavonas/química , Receptor Muscarínico M3/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transfecção
10.
Oxid Med Cell Longev ; 2019: 7187128, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30944696

RESUMO

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 µM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.


Assuntos
Antineoplásicos/uso terapêutico , Antioxidantes/uso terapêutico , Cisplatino/uso terapêutico , Melatonina/uso terapêutico , Mitocôndrias/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Apoptose , Autofagia , Cisplatino/farmacologia , Humanos , Melatonina/farmacologia , Espécies Reativas de Oxigênio , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
11.
Int J Mol Sci ; 20(6)2019 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-30875877

RESUMO

Inflammation is a central aspect of tumour biology and can contribute significantly to both the origination and progression of tumours. The NFκB pathway is one of the most important signal transduction pathways in inflammation and is, therefore, an excellent target for cancer therapy. In this work, we examined the influence of four NFκB inhibitors-Cortisol, MLN4924, QNZ and TPCA1-on proliferation, inflammation and sensitisation to apoptosis mediated by the death ligand FasL in the HNSCC cell lines PCI1, PCI9, PCI13, PCI52 and SCC25 and in the human dermal keratinocyte cell line HaCaT. We found that the selection of the inhibitor is critical to ensure that cells do not respond by inducing counteracting activities in the context of cancer therapy, e.g., the extreme IL-8 induction mediated by MLN4924 or FasL resistance mediated by Cortisol. However, TPCA1 was qualified by this in vitro study as an excellent therapeutic mediator in HNSCC by four positive qualities: (1) proliferation was inhibited at low µM-range concentrations; (2) TNFα-induced IL-8 secretion was blocked; (3) HNSCC cells were sensitized to TNFα-induced cell death; and (4) FasL-mediated apoptosis was not disrupted.


Assuntos
Anti-Inflamatórios/farmacologia , Proteína Ligante Fas/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , NF-kappa B/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Fator de Necrose Tumoral alfa/farmacologia , Amidas/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Ciclopentanos/farmacologia , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Sinergismo Farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Hidrocortisona/farmacologia , Interleucina-8/metabolismo , Éteres Fenílicos/farmacologia , Pirimidinas/farmacologia , Quinazolinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Tiofenos/farmacologia
12.
Med Oncol ; 36(5): 42, 2019 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-30927146

RESUMO

The purpose of this study is to evaluate if, in elderly HNC patients, loco-regional control (LRC) is influenced by average weekly radiation dose (AWD). From 2009 to 2017, 150 consecutive HNC elderly patients were analyzed. AWD was calculated by dividing total dose in Gray by overall treatment time in weeks. Patients were divided in 2 groups: Group 1 (70-75 years) and Group 2 (> 75 years). Primary endpoint was LRC; secondary endpoints were overall survival (OS) and compliance to treatment. The median age was 76 years (range 70-92), the distribution of patients by age was 72 and 78 patients in Group 1 and in Group 2, respectively; overall median follow-up was 23 months. Optimal cut-off of AWD for LRC was 9.236 (p = 0.018). Median OS was 73 months. In univariate survival analysis low PS (p = 0.005), T3-T4 (p = 0.021), Stage III-IV (p = 0.046) and AWDLow (< 9.236) (p = 0.018) were significantly associated with lower LRC; low PS (p < 0.001) and Group 2 (p = 0.006) were also associated with lower OS. Considering patients treated with radiotherapy alone AWDLow was significantly associated with lower LRC (p = 0.04) whereas among patient treated with chemoradiotherapy AWD did not affected LRC (p = 0.18). The multivariate analysis confirmed the significant value of PS for the prediction of LRC and OS (p = 0.035 and p < 0.001, respectively). In elderly patients an AWD of > 9.236 Gy was found to be beneficial for RT alone regimen. When radiotherapy alone is indicated in elderly patients an effort should be made to maintain an increased AWD in order to improve LRC.


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 , Idoso de 80 Anos ou mais , Cetuximab/uso terapêutico , Quimiorradioterapia/normas , Cisplatino/uso terapêutico , Progressão da Doença , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Cooperação do Paciente , Doses de Radiação , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida
13.
Crit Rev Oncol Hematol ; 135: 39-46, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819445

RESUMO

BACKGROUND: We conducted a meta-analysis to examine the associations of age, human papillomavirus (HPV) infection, and performance status with the overall survival (OS) benefits of patients with head and neck squamous cell carcinoma (HNSCC) after treatment with versus without epidermal growth factor receptor (EGFR) inhibitors. METHODS: We systematically searched literature for randomized controlled trials comparing chemotherapy or radiotherapy with versus without EGFR inhibitors in locoregionally advanced, recurrent, or metastatic HNSCCs. Hazard ratios (HRs) for OS were calculated using random-effects models for patient groups according to age (younger vs. older), HPV infection status (p16-positive vs. p16-negative), and performance status score (better vs. poorer). RESULTS: Five phase III trials with 2653 patients were included. EGFR inhibition was associated with a greater OS benefit in younger patients than in older counterparts (HR 0.70 vs. 1.05, P < 0.001). There were no apparent differences in OS based on HPV status (P = 0.860) or performance status score (P = 0.235). Largely consistent results were obtained following stratification by treatment strategy (i.e., chemotherapy and radiotherapy). CONCLUSIONS: Patient age appears to impact OS independent of HPV infection and performance status after adding EGFR inhibitor agents during HNSCC treatment. This finding may help design relevant clinical trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Adulto , Fatores Etários , Idoso , Cetuximab/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Feminino , Gefitinibe/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Panitumumabe/uso terapêutico , Infecções por Papillomavirus/epidemiologia , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
14.
Oncol Rep ; 41(5): 2615-2624, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30896830

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is the sixth most commonly diagnosed cancer worldwide. It has poor clinical outcome due to intrinsic or acquired drug resistance. Deregulation of both apoptosis and autophagy contributes to chemotherapy resistance and disease progression. A new member of the inhibitors of apoptosis protein (IAP) family, namely survivin, is selectively overexpressed in tumors, including HNSCC, but not in normal tissues. Thus, it is considered a tumor biomarker. Here, we reviewed survivin expression and function in tumor progression focusing on its nodal role in the regulation of cell apoptosis and autophagy. Based on literature data, survivin targeting may be envisaged as a novel therapeutic strategy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Survivina/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Biomarcadores Tumorais/antagonistas & inibidores , Ciclo Celular/efeitos dos fármacos , Ensaios Clínicos como Assunto , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Terapia de Alvo Molecular/métodos , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/prevenção & controle , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Survivina/antagonistas & inibidores , Resultado do Tratamento
16.
Mol Pharmacol ; 95(5): 528-536, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30858165

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is a common and debilitating form of cancer characterized by poor patient outcomes and low survival rates. In HNSCC, genetic aberrations in phosphatidylinositol 3-kinase (PI3K) and epidermal growth factor receptor (EGFR) pathway genes are common, and small molecules targeting these pathways have shown modest effects as monotherapies in patients. Whereas emerging preclinical data support the combined use of PI3K and EGFR inhibitors in HNSCC, in-human studies have displayed limited clinical success so far. Here, we examined the responses of a large panel of patient-derived HNSCC cell lines to various combinations of PI3K and EGFR inhibitors, including EGFR agents with varying specificity and mechanistic characteristics. We confirmed the efficacy of PI3K and EGFR combination therapies, observing synergy with α isoform-selective PI3K inhibitor HS-173 and irreversible EGFR/ERBB2 dual inhibitor afatinib in most models tested. Surprisingly, however, our results demonstrated only modest improvement in response to HS-173 with reversible EGFR inhibitor gefitinib. This difference in efficacy was not explained by differences in ERBB target selectivity between afatinib and gefitinib; despite effectively disrupting ERBB2 phosphorylation, the addition of ERBB2 inhibitor CP-724714 failed to enhance the effect of HS-173 gefitinib dual therapy. Accordingly, although irreversible ERBB inhibitors showed strong synergistic activity with HS-173 in our models, none of the reversible ERBB inhibitors were synergistic in our study. Therefore, our results suggest that the ERBB inhibitor mechanism of action may be critical for enhanced synergy with PI3K inhibitors in HNSCC patients and motivate further preclinical studies for ERBB and PI3K combination therapies.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Afatinib/farmacologia , Linhagem Celular Tumoral , Inibidores Enzimáticos/farmacologia , Receptores ErbB/antagonistas & inibidores , Gefitinibe/farmacologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Piridinas/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Sulfonamidas/farmacologia
17.
Ann Otol Rhinol Laryngol ; 128(7): 595-600, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30808209

RESUMO

OBJECTIVES: The aim of this study was to investigate the utility of pretreatment and 3-month 18F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) standardized uptake value (SUV) in predicting and assessing recurrence in T3-T4 laryngeal carcinoma treated with definitive radiation therapy (RT). METHODS: Patients with newly diagnosed T3-T4 laryngeal squamous cell carcinoma treated with definitive RT from 2004 to 2014 were reviewed. Patients who underwent pretreatment or 3-month PET/CT 2 to 4 months after treatment were included. Those with prior systemic, surgical, or RT treatment were excluded. The primary objective was to assess whether pretreatment or posttreatment maximum SUV of the primary site (pSUV) of disease was associated with local recurrence-free survival. Overall survival was a secondary end point. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated to assess the accuracy of 3-month PET/CT at the larynx primary. RESULTS: Twenty-eight patients were eligible for analysis. Median follow-up time was 34.7 months (range, 5.3-138.7 months), and median age was 57 years. Most patients had supraglottic (71.4%), T3 (89.3%), N2 (50.0%) disease, received chemotherapy (96.4%), and had histories of tobacco use (96.4%). On univariate analysis, 3-month posttreatment pSUV was associated with local recurrence-free survival ( P < .01), while pretreatment pSUV was not ( P = .41). No other associations were found with local recurrence-free survival. Neither pretreatment nor 3-month pSUV was significantly associated with overall survival. The calculated sensitivity, specificity, positive predictive value, and negative predictive value of 3-month PET/CT at the primary site were 33%, 85%, 40%, and 81%, respectively. CONCLUSIONS: High initial fluorodeoxyglucose uptake in T3-T4 laryngeal primaries did not show an association with the risk for postradiation local relapse or overall survival, while increased fluorodeoxyglucose uptake at 3 months was associated with increased local recurrence. At 3 months, the relatively low sensitivity and positive predictive value may limit the utility of PET/CT in the assessment of persistent advanced laryngeal cancer after definitive radiation.


Assuntos
Neoplasias Laríngeas/diagnóstico por imagem , Recidiva Local de Neoplasia/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Adulto , Idoso , Antineoplásicos/uso terapêutico , Intervalo Livre de Doença , Feminino , Fluordesoxiglucose F18 , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Neoplasias Laríngeas/tratamento farmacológico , Neoplasias Laríngeas/patologia , Neoplasias Laríngeas/radioterapia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Prognóstico , Modelos de Riscos Proporcionais , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
18.
Gan To Kagaku Ryoho ; 46(1): 21-27, 2019 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-30765636

RESUMO

Recent breakthrough in cancer immunotherapy employing immune checkpoint inhibitors(ICI)has evolved into number of clinical trials with antibodies against PD-1, PD-L1, and CTLA-4 for patients with squamous cell carcinoma of head and neck (SCCHN). The development of ICI in SCCHN initiated in the recurrent and metastatic setting. CheckMate141 supports nivolumab as a standard therapy for patients with platinum-refractory recurrent and metastatic-SCCHN. KEYNOTE-048 testing pembrolizumab demonstrated future practice-changing data in platinum sensitive recurrent and metastatic-SCCHN. ICI may open the door to a new era of tailor-made medicine in treatment of recurrent and metastatic-SCCHN, based on tumor burden, clinical stability, and PD-L1 status. Furthermore, ICI in combination with concurrent cisplatin based chemoradiotherapy has been investigated for locoregionally advanced disease.


Assuntos
Neoplasias de Cabeça e Pescoço , Imunoterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Quimiorradioterapia , Cisplatino , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia
19.
Acta Otolaryngol ; 139(2): 201-205, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30794080

RESUMO

BACKGROUND: Combination therapy consisting of a platinum agent, 5-fluorouracil and cetuximab (EXTREME regimen) is recommended for recurrent or metastatic squamous cell carcinoma of the head and neck (R/M-SCCHN). However, it is advisable to use platinum-free regimens as first-line therapy in patients resistant to platinum agents. There has been no report comparing EXTREME regimen outcomes between platinum-resistant and platinum-sensitive patients. OBJECTIVES: We conducted this study to examine the outcomes of the EXTREME regimen as first-line therapy in patients with R/M-SCCHN and a history of platinum agent use and assess whether the EXTREME regimen outcomes differ between platinum-resistant and platinum-sensitive patients. MATERIALS AND METHODS: The study included 32 patients with R/M-SCCHN who received the EXTREME regimen as first-line therapy. Patients with recurrence or metastasis within 6 months after cisplatin administration were considered platinum-resistant and those with no recurrence or metastasis within 6 months were considered platinum-sensitive. RESULTS: 17 patients were platinum-resistant and 15 patients were platinum-sensitive. The median survival durations were 10.6 and 19.9 months in the platinum-resistant and platinum-sensitive patients, respectively, and the prognosis was significantly better in the platinum-sensitive patients (p = .02). CONCLUSIONS: Our findings suggest that the EXTREME regimen is useful as first-line therapy for R/M-SCCHN in platinum-sensitive patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carboplatina/administração & dosagem , Cetuximab/administração & dosagem , Cisplatino/administração & dosagem , Estudos de Coortes , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos , Feminino , Fluoruracila/administração & dosagem , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Invasividade Neoplásica/patologia , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Medição de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Estatísticas não Paramétricas , Análise de Sobrevida , Resultado do Tratamento
20.
Cir Cir ; 87(2): 141-145, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30768062

RESUMO

Introduction: Patients with bulky metastases of squamous cell carcinoma of the head and neck represent a challenge for the therapeutic decision; balance between oncological control and complications should be achieved. The therapeutic sequence has no impact on survival but sequelae. Objective: We analyze the oncological results in patients with bulky metastases on the neck treated with induction chemotherapy and with up-front neck dissection. Method: Retrospective analysis of patients undergoing treatment for cervical lymph node metastasis of squamous cell carcinoma; The therapeutic sequence was decided based on volume, resectability, site, and size of the primary and general condition of the patient. Overall survival was calculated based on human papilloma virus (HPV) status. Results: There were 30 patients, 22 men and eight women with a mean age of 57 years, 10 N3 and 20 N2. In 13 the HPV was positive, in 5 negative and in 12 the determination was not made. Seven patients were treated with initial chemotherapy, and 23 underwent neck dissection; the 5-year survival was 25%, and the prognosis was better in the positive HPV. Conclusion: The treatment of cervical metastasis depends on the possibility of resection. We should favor the initial surgery. The HPV is a factor of good prognosis.


Assuntos
Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/cirurgia , Quimioterapia de Indução , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Quimiorradioterapia , Terapia Combinada/métodos , Feminino , Neoplasias de Cabeça e Pescoço/secundário , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Esvaziamento Cervical , Papillomaviridae/isolamento & purificação , Complicações Pós-Operatórias/prevenção & controle , Estudos Retrospectivos , Terapia de Salvação , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Análise de Sobrevida
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