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1.
Artigo em Inglês | MEDLINE | ID: mdl-32144570

RESUMO

PURPOSE: Granulomatous inflammation is a common cause of subacute cervicofacial lymphadenitis in children. Nontuberculous mycobacterial (NTM) infections and cat-scratch disease (CSD) are the most frequent causes. Optimal treatment, which may include surgery, antibiotic treatment or wait-and-see approach, is debatable. The goal of this study was to compare the short- and long-term outcome of various surgical procedures. METHODS: Case series with a chart review of all children treated by surgical excision of granulomatous lymph nodes in the cervicofacial area from 2000 to 2016 at two tertiary care centers. RESULTS: Forty patients were included in this study. The median age at first symptoms was 3.7 years (13 months-14 years). Mean follow-up was 5.8 years (6 months-15.3 years). 25 patients fit with diagnosis of NTM infection, 6 with CSD while diagnosis remained uncertain in 9 patients. The primary surgical procedure consisted of total excision (n = 27), incision/drainage (n = 9) or incomplete excision (n = 4). None of the patients treated by primary complete excision needed further intervention contrary to the group of patients with incomplete surgical procedures where additional surgical management was required in 54%. At follow-up, all patients were healthy without evidence of recurrence. CONCLUSION: We advocate early surgical intervention with complete excision to reach quick resolution and reduce the need for additional surgery. The long-term outcome was favorable.

2.
Mol Cancer Ther ; 19(3): 777-789, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31924739

RESUMO

Cell-cycle pathway impairments resulting in CDK4 and 6 activation are frequently observed in human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN). We investigated the activity of ribociclib, a CDK4/6 inhibitor, in SCCHN models with the aim of identifying predictive biomarkers of response. HPV-negative or HPV-positive SCCHN cell lines (n = 8) and patient-derived tumor xenograft (PDTX) models (n = 6) were used. The models were classified according to their sensitivity to ribociclib to investigate potential predictive biomarkers. Ribociclib had a cytostatic effect in some HPV-negative SCCHN models but had no effect in HPV-positive models. In SCCHN cell lines and PDTXs, the retinoblastoma (Rb) protein expression level correlated with ribociclib activity. Rb knockdown was, however, not sufficient to block G0-G1 arrest induced by ribociclib in Detroit-562 where p107, p130, and Forkhead BOX M1 (FOXM1) were also implicated in ribociclib activity. Cell lines harboring epithelial-to-mesenchymal transition (EMT) features were less sensitive to ribociclib than those with an epithelial phenotype. Rb downregulation induced EMT in our Rb-expressing SCCHN cell lines. However, ribociclib still had significant activity in one PDTX model with high Rb and vimentin expression, suggesting that the presence of vimentin alone is not enough to induce ribociclib resistance. These findings suggest that CDK4/6 inhibitors should be investigated in patients with HPV-negative SCCHN with high Rb expression and an epithelial phenotype. Although these biomarkers are not predictive in all cases, they may enrich the population that could benefit from CDK4/6 inhibitors.

3.
Clin Cancer Res ; 2019 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831557

RESUMO

Optimal head and neck squamous cell carcinoma (HNSCC) patient selection for anti-EGFR-based therapy remains an unmet need since only a minority of patients derive long-term benefit from cetuximab treatment. We assessed the ability of state-of-the-art noninvasive in vivo metabolic imaging to probe metabolic shift in cetuximab-sensitive and -resistant HNSCC patient-derived tumor xenografts (PDTXs). METHODS: Three models selected based on their known sensitivity to cetuximab in patients (cetuximab-sensitive or acquired-resistant HNC007 PDTXs, cetuximab-naïve UCLHN4 PDTXs, and cetuximab-resistant HNC010 PDTXs) were inoculated in athymic nude mice. RESULTS: Cetuximab induced tumor size stabilization in mice for 4 weeks in cetuximab-sensitive and -naïve models treated with weekly injections (30 mg/kg) of cetuximab. Hyperpolarized 13C-pyruvate-13C-lactate exchange was significantly decreased in vivo in cetuximab-sensitive xenograft models 8 days after treatment initiation, whereas it was not modified in cetuximab-resistant xenografts. Ex vivo analysis of sensitive tumors resected at day 8 after treatment highlighted specific metabolic changes, likely to participate in the decrease in the lactate to pyruvate ratio in vivo. Diffusion MRI showed a decrease in tumor cellularity in the HNC007-sensitive tumors, but failed to show sensitivity to cetuximab in the UCLHN4 model. CONCLUSIONS: This study constitutes the first in vivo demonstration of cetuximab-induced metabolic changes in cetuximab-sensitive HNSCC PDTXs that were not present in resistant tumors. Using metabolic imaging, we were able to identify hyperpolarized 13C-pyruvate as a potential marker for response and resistance to the EGFR inhibitor in HNSCC.

4.
Biomark Res ; 7: 14, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31346466

RESUMO

Background: The epidermal growth factor receptor (EGFR) monoclonal IgG1 antibody cetuximab is approved for first-line treatment of recurrent and metastatic (R/M) HNSCC as a part of the standard of care EXTREME regimen (platinum/5-fluorouracil/cetuximab). This regimen has relatively high response and disease control rates but is generally not curative and many patients will experience recurrent disease and/or metastasis. Therefore, there is a great need to identify predictive biomarkers for recurrence and disease progression in cetuximab-treated HNSCC patients to facilitate patient management and allow for treatment modification. The goal of this work is to assess the potential of activating interleukin-1 (IL-1) ligands (IL-1 alpha [IL-1α], IL-1 beta [IL-1ß]) as predictive biomarkers of survival outcomes in HNSCC patients treated with cetuximab-based chemotherapy. Methods: Baseline gene, serum and tumor expression of interleukin-1 (IL-1) ligands were analyzed from The Cancer Genome Atlas (TCGA) database or clinical trials of cetuximab-based therapies and interrogated for associations with clinical outcome data. Results: High tumor gene expression of IL-1ß was associated with a more favorable overall survival in cetuximab-treated HNSCC patients but not in non-cetuximab-treated patients. In HNSCC patients treated with cetuximab-based chemotherapy, higher gene and circulating levels of IL-1α and IL-1ß were correlated with a more favorable progression free survival compared to patients with low or undetectable levels of IL-1 ligands. Conclusions: These findings suggest that IL-1 ligands may function as predictive biomarkers for tumor response to cetuximab-based chemotherapy in HNSCC patients and warrants further investigation and validation in larger clinical studies.

5.
Eur J Surg Oncol ; 45(7): 1188-1195, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30940421

RESUMO

INTRODUCTION: The aim of this study was to assess the validity of a treatment strategy for T1N0 glottic squamous cell carcinoma. METHODS: One hundred and seventeen patients were prospectively treated according to institutional guidelines. using 1) laser microsurgery (L) for exophytic tumor, limited to one vocal cord, without extension to the anterior commissure or the vocal process of the arytenoid cartilage, 2) radiotherapy (RT) for large or infiltrative tumor reaching the anterior commissure or the vocal process of the arytenoid cartilage, poor endoscopic exposure and cT1b or 3) partial laryngectomy (PL) for tumor infiltrating the anterior commissure. Ninety-five patients were treated with RT and 22 with surgery alone (S) [L:19; PL:3]. RESULTS: The 5-year overall survival (OS) and disease-specific survival (DSS) were 81.5% and 97.1% (median follow-up: 73 months), respectively. There was no statistically significant difference in OS or DSS between patients treated with RT or S (logrank test: p = 0.974 and 0.978). The 5-year ultimate local control rate reached 98.3%. The local control rate with larynx preservation was 94.9% with no difference between RT (94.7%) and S (95.5%) (χ2: p = 0.891). Continued smoking after RT was significantly associated with a lower 5-year OS (77.9% versus 87%), [HR 3.458; p = 0.043 (95%CI 1.010-11.837)]. CONCLUSIONS: For patients with T1 glottic carcinoma, and based on our previous studies, these data prospectively confirm the oncologic validity of an institutional treatment strategy. Continued smoking after RT correlated with poor OS.

6.
Front Oncol ; 9: 155, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30941307

RESUMO

Background: The majority of human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN) present upregulation of the epidermal growth factor receptor (EGFR) and frequent alterations in the cyclin D1-cyclin dependent kinase (CDK) 4/6 (CDK 4/6)-retinoblastoma protein (pRb) pathway, resulting in cell cycle progression and tumor proliferation. This study investigated the combination of ribociclib, an orally highly selective inhibitor of CDK 4/6, and cetuximab in recurrent and/or metastatic (R/M) SCCHN. Methods: A phase I trial using a 3 + 3 design was performed to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of ribociclib with standard dose of weekly cetuximab in HPV-negative patients with R/M SCCHN. Ribociclib was administered orally (3 weeks on/1 week off) at dose level 1 of 400 mg daily and dose level 2 of 600 mg daily. The MTD of ribocilib was then further evaluated in an expansion cohort. Results: 10 patients were enrolled in the escalation trial. No DLTs were observed at dose level 1 (n = 3); at dose level 2, one patient was replaced due to rapid disease progression, and one patient out of six evaluable patients experienced a DLT (grade 4 thrombocytopenia >7 days). Ribociclib 600 mg daily was thus determined to be the MTD. Eleven additional patients were enrolled in the expansion cohort. Diarrhea (52%), rash (52%), fatigue (43%), nausea (33%), and mucositis (28%) were the most frequent grade 1-2 adverse events (AE). Neutropenia was the most frequent grade 3-4 AE (20%). Median progression-free survival (PFS) was 3.5 months (range 0.4-17.3 months) and median overall survival (OS) was 8.3 months (range 0.4-24.1 months). Among the 19 radiologically evaluable patients, two (10.5%) achieved a partial response and 11 (58%) had stable disease. Conclusions: The MTD of ribociclib is 600 mg daily when administered in combination with standard dose cetuximab for 3 weeks on and 1 week off. This combination was safe and showed efficacy. Further clinical trials should be conducted to evaluate the antitumor effects of this combination. Trial Information: ClinicalTrials.gov: NCT02429089; Eudract number 2014-005371-83.

7.
Orphanet J Rare Dis ; 13(1): 191, 2018 10 29.
Artigo em Inglês | MEDLINE | ID: mdl-30373605

RESUMO

BACKGROUND: Extensive and complex vascular malformations often cause chronic pain and severe functional restraint. Conventional treatments, such as surgery and/or sclerotherapy, are rarely curative, underscoring the great need for new therapeutic modalities. Recent preclinical and clinical data demonstrated that sirolimus could offset the progression of vascular malformations and significantly improve quality of life of patients through inhibition of the Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian Target of Rapamycin (mTOR) pathway. The purpose of this prospective study was to assess the efficacy and safety of this treatment in patients with extensive or complex slow-flow vascular malformations. METHODS: Sirolimus was administered orally on a continuous dosing schedule with pharmacokinetic-guided target serum concentration level of 10 to 15 ng/ml. Patients were seen every month for the first three months and subsequently every three months. The primary endpoints were safety and efficacy, based on clinical, biological and radiological evaluations, as well as a quality of life questionnaire. RESULTS: Nineteen patients, from 3 to 64 years old, with lymphatic (LM), venous (VM) or complex slow-flow malformations, refractory to standard care, were enrolled and received sirolimus continuously. After 12 months of follow-up, 16 patients were available for assessment of efficacy and safety: all had a significant and rapid improvement of their symptoms and quality of life. In two patients, sirolimus treatment permitted sclerotherapy and surgery, initially evaluated unfeasible. Sirolimus was well tolerated, with mucositis as the most common (10% of patients) grade 3 adverse event. CONCLUSIONS: Sirolimus was efficient in extensive LM, VM and/or complex malformations that were refractory to conventional treatments and was well tolerated.


Assuntos
Imunossupressores/uso terapêutico , Sirolimo/uso terapêutico , Malformações Vasculares/tratamento farmacológico , Adolescente , Adulto , Criança , Pré-Escolar , Esquema de Medicação , Feminino , Humanos , Imunossupressores/administração & dosagem , Masculino , Pessoa de Meia-Idade , Sirolimo/administração & dosagem , Resultado do Tratamento , Adulto Jovem
8.
Eur J Cancer ; 104: 219-223, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30301582

RESUMO

Assessing tumour response using a traditional phase I, II and III trial approach is not without limitations, particularly when targeted therapies are involved. Window of opportunity trials, performed presurgically but differing from neoadjuvant studies, were developed in an attempt to overcome the limitations of the traditional approach. A recent window of opportunity trial, the EORTC 90111-24111-NOCI-HNCG study, evaluated afatinib in treatment-naive patients with squamous cell carcinoma of the head and neck. While this study was the first to demonstrate the activity of afatinib in this setting and to define its potential predictive biomarkers, it also highlighted the challenges associated with the window of opportunity trial design, including the impact of patient selection, tumour site, and other organisational issues. This report details the key learnings from the EORTC 90111-24111-NOCI-HNCG study and provides recommendations to overcome the challenges of this particular trial design.


Assuntos
Afatinib/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Ensaios Clínicos Fase II como Assunto/métodos , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Estudos Multicêntricos como Assunto/métodos , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Afatinib/administração & dosagem , Afatinib/farmacocinética , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Biomarcadores Tumorais/análise , Carcinoma de Células Escamosas/química , Carcinoma de Células Escamosas/diagnóstico por imagem , Carcinoma de Células Escamosas/cirurgia , Neoplasias de Cabeça e Pescoço/química , Neoplasias de Cabeça e Pescoço/diagnóstico por imagem , Neoplasias de Cabeça e Pescoço/cirurgia , Humanos , Comunicação Interdisciplinar , Imagem por Ressonância Magnética/métodos , Equipe de Assistência ao Paciente , Seleção de Pacientes , Pré-Medicação , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Garantia da Qualidade dos Cuidados de Saúde , Projetos de Pesquisa , Manejo de Espécimes , Fatores de Tempo , Tomografia Computadorizada por Raios X
9.
Cancers (Basel) ; 10(8)2018 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-30103407

RESUMO

Chemoradiotherapy has emerged as a gold standard in advanced squamous cell carcinoma of the head and neck (SCCHN). Because 50% of advanced stage patients relapse after nonsurgical primary treatment, the role of salvage surgery (SS) is critical because surgery is generally regarded as the best treatment option in patients with recurrent resectable SCCHN. Surgeons are increasingly confronted with considering operation among patients with significant effects of failed non-surgical primary treatment. Wide local excision to achieve clear margins must be balanced with the morbidity of the procedure, the functional consequences of organ mutilation, and the likelihood of success. Accurate selection of patients suitable for surgery is a major issue. It is essential to establish objective criteria based on functional and oncologic outcomes to select the best candidates for SS. The authors propose first to understand preoperative prognostic factors influencing survival. Predictive modeling based on preoperative information is now available to better select patients having a good chance to be successfully treated with surgery. Patients with a high comorbidity index, advanced oropharyngeal or hypopharyngeal primary tumors, and both local and regional recurrence have a very limited likelihood of success with salvage surgery and should be strongly considered for other treatments. Following SS, identifying patients with postoperative prognostic factors predicting high risk of recurrence is essential because those patients could benefit of adjuvant treatment or be included in clinical trials. Finally, defining HPV tumor status is needed in future studies including recurrent oropharyngeal SCC patients.

10.
Oncotarget ; 9(47): 28572-28585, 2018 Jun 19.
Artigo em Inglês | MEDLINE | ID: mdl-29983881

RESUMO

We investigated changes on 2'-deoxy-2'-[18F]fluoro-D-glucose positron emission tomography (18FDG-PET), diffusion-weighted magnetic resonance imaging (DW-MRI), and choline spectroscopy as early markers of cetuximab activity in squamous cell carcinoma of the head and neck (SCCHN). SCCHN patient-derived tumor xenografts models were selected based on their cetuximab sensitivity. Three models were resistant to cetuximab and two were sensitive (one was highly sensitive and the other one was moderately sensitive). Cetuximab was infused on day 0 and 7. Maximal standardized uptake values (SUVmax), apparent diffusion coefficient (ADC), and total choline pool were measured at baseline and at day 8. To investigate the possible clinical relevance of our pre-clinical findings, we also studied the SUVmax and ADC modifications induced by cetuximab in five patients. Cetuximab induced a significant decrease in SUVmax and an increase in ADC at day 8 compared to baseline in the most cetuximab-sensitive model but not in the other models. At day 8, in one resistant model, SUVmax was decreased compared to baseline and was significantly lower than the controls. Choline spectroscopy was not able to predict cetuximab activity. The five patients treated with cetuximab had a 18FDG-PET partial response. One patient had a partial response according to RECISTv1.1. Interestingly, this last had also an increase in ADC value above 25%. Our preclinical data support the use of PDTX to investigate imaging techniques to detect early treatment response. Our pre-clinical and clinical data suggest that DW-MRI and 18FDG-PET should be further investigated to predict cetuximab activity.

11.
Genome Med ; 10(1): 37, 2018 05 23.
Artigo em Inglês | MEDLINE | ID: mdl-29792227

RESUMO

BACKGROUND: Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients' treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. METHODS: To determine the dynamics of these molecular changes, we obtained high throughput omics data (RNA-sequencing and DNA methylation) weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. The CoGAPS unsupervised algorithm was used to determine the dynamics of the molecular changes associated with resistance during the time course of resistance development. RESULTS: CoGAPS was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. CONCLUSIONS: Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize the resistant phenotype. These genes include FGFR1, which was associated with EGFR inhibitors resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. This understanding of the time course progression of molecular changes in acquired resistance is important for the development of alternative treatment strategies that would introduce appropriate selection of new drugs to treat cancer before the resistant phenotype develops.


Assuntos
Resistencia a Medicamentos Antineoplásicos/genética , Genômica , Algoritmos , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Células Clonais , Metilação de DNA/efeitos dos fármacos , Metilação de DNA/genética , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Epigênese Genética/efeitos dos fármacos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/genética , Humanos , Neoplasias de Células Escamosas/genética , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/metabolismo , Fatores de Tempo , Resultado do Tratamento
12.
J Otolaryngol Head Neck Surg ; 47(1): 38, 2018 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-29801509

RESUMO

BACKGROUND: Providing adequate ventilation may remain complex in patients with severe proximal laryngotracheal stenosis, especially when the airway is shared with the surgeon during tracheal resection surgery. We describe an effective alternative to standard endotracheal intubation using a Rüsch flexible intubation guide catheter. METHODS: In two patients undergoing tracheal repair surgery, we failed to insert a 5.0 inner diameter endotracheal tube (6.9 mm outer diameter) or a 6.0 mm outer diameter endoscope through the laryngotracheal stenosis. However, using indirect laryngoscopy, a 6.0 outer diameter Rüsch flexible intubation guide catheter was passed successfully through the vocal cords and then through the stenosis. Controlled ventilation was achieved by means of the Rüsch guide, provided with its two large Murphy's eyes. When the trachea was opened, the Rüsch guide was removed just enough for the surgeons to place a Montandon tracheal tube, at that point taking over ventilation. A 7.0 inner diameter endotracheal cuffed tube had been inserted onto the Rüsch guide and left pending upstream from the vocal cords. Once the posterior tracheal wall was sutured, this endotracheal cuffed tube was slid along the Rüsch guide through the vocal cords with the cuff placed beyond the tracheal sutures. RESULTS: Controlled ventilation through the Rüsch flexible intubation guide catheter showed satisfying and stable ventilatory parameters in both patients. Inspiratory pressures of 25-30 mmHg were enough to reach adequate tidal volumes around 450 ml. End tidal CO2 was kept between 35 and 40 mmHg (PaCO2 showed similar values). Standard endotracheal intubation at the end of the tracheal resection was easy and safe thanks to the Rüsch guide still in place between the vocal cords. CONCLUSIONS: We suggest an effective and reliable method using a Rüsch flexible intubation guide catheter for airway management in patients suffering from laryngotracheal stenosis in the setting of tracheal repair surgery.


Assuntos
Cateteres , Intubação Intratraqueal/instrumentação , Laringoestenose/cirurgia , Estenose Traqueal/cirurgia , Adulto , Idoso , Feminino , Humanos , Intubação Intratraqueal/métodos , Respiração Artificial
13.
EMBO Rep ; 19(1): 118-134, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29141987

RESUMO

T-box transcription factors play essential roles in multiple aspects of vertebrate development. Here, we show that cooperative function of BRACHYURY (T) with histone-modifying enzymes is essential for mouse embryogenesis. A single point mutation (TY88A) results in decreased histone 3 lysine 27 acetylation (H3K27ac) at T target sites, including the T locus, suggesting that T autoregulates the maintenance of its expression and functions by recruiting permissive chromatin modifications to putative enhancers during mesoderm specification. Our data indicate that T mediates H3K27ac recruitment through a physical interaction with p300. In addition, we determine that T plays a prominent role in the specification of hematopoietic and endothelial cell types. Hematopoietic and endothelial gene expression programs are disrupted in TY88A mutant embryos, leading to a defect in the differentiation of hematopoietic progenitors. We show that this role of T is mediated, at least in part, through activation of a distal Lmo2 enhancer.


Assuntos
Desenvolvimento Embrionário/genética , Proteínas Fetais/genética , Histonas/metabolismo , Mesoderma/metabolismo , Células-Tronco Embrionárias Murinas/metabolismo , Proteínas com Domínio T/genética , Fatores de Transcrição de p300-CBP/genética , Acetilação , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Sequência de Bases , Diferenciação Celular , Linhagem da Célula/genética , Cromatina/química , Cromatina/metabolismo , Embrião de Mamíferos , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Proteínas Fetais/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Loci Gênicos , Células-Tronco Hematopoéticas/citologia , Células-Tronco Hematopoéticas/metabolismo , Histonas/genética , Proteínas com Domínio LIM/genética , Proteínas com Domínio LIM/metabolismo , Mesoderma/citologia , Mesoderma/crescimento & desenvolvimento , Camundongos , Células-Tronco Embrionárias Murinas/citologia , Mutação Puntual , Ligação Proteica , Transdução de Sinais , Proteínas com Domínio T/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo
14.
Cancer Biol Ther ; 18(10): 775-782, 2017 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-28886272

RESUMO

The tumor suppressor gene TP53 is the most frequently mutated gene in human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC). It represents a known transcription factor that controls different microRNAs (miRNA) and target genes involved in the regulation of cellular stress, apoptosis and response to DNA damage. We used The Cancer Genome Atlas database to investigate the difference in transcriptome and proteome levels between mutated and wild-type TP53 HPV-negative HNSCC. Using different databases and an extensive literature review, we built the transcriptional and post-transcriptional network regulated by TP53. TP53 mutation was associated with poor overall survival in 203 HPV-negative patients compared to 40 patients with TP53 wild-type tumors. Using the enrichment analysis, we found that UHRF1BP1 and SESN1 mRNA were linked to prognosis in the TP53 mutated group. This is also the case for miR-377-3p, an important miRNA regulator of SESN1. Our study shows that SESN1 mRNA, UHRF1BP11 mRNA and miRNA-377-3p levels are prognostically relevant in HPV-negative HNSCC patients. This finding may help with patient stratification and the development of potential new therapeutic targets to treat patients with HNSCC.


Assuntos
Carcinoma de Células Escamosas/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Proteínas de Choque Térmico/genética , MicroRNAs/metabolismo , Proteína Supressora de Tumor p53/genética , Idoso , Carcinoma de Células Escamosas/mortalidade , Biologia Computacional , Conjuntos de Dados como Assunto , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Redes Reguladoras de Genes/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Proteínas de Choque Térmico/metabolismo , Humanos , Estimativa de Kaplan-Meier , Masculino , MicroRNAs/genética , Mutação , Prognóstico , RNA Mensageiro/metabolismo , Medição de Risco/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço , Proteína Supressora de Tumor p53/metabolismo
15.
Oral Oncol ; 67: 1-9, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28351561

RESUMO

OBJECTIVE: Salvage surgery in recurrent SCCHN is associated with poor outcomes. This study aimed to better identify suitable surgical candidates and those at high risk of new recurrence. MATERIALS AND METHODS: Single-center retrospective analysis of 109 patients undergoing salvage surgery for recurrent SCCHN. Univariate and multivariate analyses were used to identify prognostic factors affecting disease-free survival (DFS). RESULTS: The following factors showed a significant impact on DFS: Disease-free interval >6months [HR 0.53; p=0.04], age>70years [HR 0.26; p=0.03], primary chemoradiotherapy [HR 2.39; p<0.01] compared to radiotherapy, oropharynx [HR 5.46; p<0.01] and hypopharynx [HR 3.92; p=<0.01] sites, compared to larynx, initial stage III [HR 7.10; p<0.01] and stage IV [HR 4.13; p<0.01], compared to stage I, locoregional recurrence [HR 4.57; p<0.01], compared to local recurrence. Univariate analysis also identified significant postoperative predictors of poor DFS including flap reconstruction [HR 3.44; p<0.01], postoperative complications [HR 2.09; p=0.01], positive margins [HR 3.64; p<0.01] and close margins [HR 3.83; p<0.01]. On multivariate analysis, oropharynx site [HR 3.98; p<0.01], initial stage III [HR 5.93; p<0.01] and locoregional recurrence [HR 2.93; p=0.04] were independent preoperative prognostic factors for DFS. Positive margins [HR 2.32; p=0.04], close margins [HR 2.94; p=0.02], extracapsular spread (ECS) [HR 4.04; p=0.03] and postoperative complications [HR 3.64; p<0.01] were independent postoperative prognostic factors. CONCLUSIONS: Patients with advanced primary nonlaryngeal tumor and locoregional recurrence have limited success with salvage surgery. Because patients with positive margins and ECS are at high risk of relapse, adjuvant treatment should be discussed.


Assuntos
Carcinoma de Células Escamosas/cirurgia , Neoplasias de Cabeça e Pescoço/cirurgia , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Carcinoma de Células Escamosas de Cabeça e Pescoço , Resultado do Tratamento
16.
Oncologist ; 21(12): 1416-e17, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27903924

RESUMO

LESSONS LEARNED: Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. For the first time, cabazitaxel was investigated in incurable patients with recurrent SCCHN. Patients were randomly assigned to cabazitaxel every 3 weeks or weekly methotrexate.This phase II study did not meet its primary endpoint.Cabazitaxel has low activity in SCCHN.The toxicity profile in this population also was not favorable owing to the high rate of febrile neutropenia observed (17%). BACKGROUND: Cabazitaxel is a second-generation taxane that improves the survival of patients with metastatic castrate-resistant prostate cancer following docetaxel therapy. Cabazitaxel has activity in squamous cell carcinoma of the head and neck (SCCHN) and taxane-resistant cell lines. In this randomized phase II trial, we investigated cabazitaxel in patients with recurrent SCCHN. METHODS: Patients with incurable SCCHN with progression after platinum-based therapy were randomly assigned to cabazitaxel every 3 weeks (cycle 1, 20 mg/m2, increased to 25 mg/m2 for subsequent cycles in the absence of nonhematological adverse events [AEs] greater than grade 2 and hematological AEs greater than grade 3) or methotrexate (40 mg/m2/week). The patients were stratified according to their performance status and previous platinum-based chemotherapy for palliation versus curative intent. The primary endpoint was the progression-free survival rate (PFSR) at 18 weeks. RESULTS: Of the 101 patients, 53 and 48, with a median age of 58.0 years (range, 41-80), were randomly assigned to cabazitaxel or methotrexate, respectively. The PFSR at 18 weeks was 13.2% (95% confidence interval [CI], 5%-25%) for cabazitaxel and 8.3% (95% CI, 2%-20%) for methotrexate. The median progression-free survival was 1.9 months in both arms. The median overall survival was 5.0 and 3.6 months for cabazitaxel and methotrexate, respectively. More patients experienced serious adverse events with cabazitaxel than with methotrexate (54% vs. 36%). The most common drug-related grade 3-4 AE in the cabazitaxel arm was febrile neutropenia (17.3%). CONCLUSION: This study did not meet its primary endpoint. Cabazitaxel has low activity in recurrent SCCHN.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Metotrexato/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Taxoides/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/mortalidade , Feminino , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Metotrexato/efeitos adversos , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxoides/efeitos adversos
17.
J Clin Anesth ; 32: 142-7, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27290963

RESUMO

INTRODUCTION: The authors modified an adult jet ventilation injector (Hunsaker Mon-Jet Ventilation Tube(®)) to be able to provide transglottal high-frequency jet ventilation (HFJV) in small children undergoing laryngeal procedures with CO2 laser. METHODS AND MATERIAL: Retrospective review of the anesthetic records of all children younger than 2years undergoing transglottal HFJV for CO2 laser laryngeal procedures using this modified adult injector between 2006 and 2013. RESULTS: Nine children (5 boys, 4 girls) were identified who underwent a total of 20 procedures. Mean age was 7.4 ± 6.9months, and mean weight was 6 ± 2.8 kg. No complications were observed with the use of HFJV or this modified injector. CONCLUSION: In experienced hands, this modified injector ensures excellent visibility and field access to the surgeon as well as adequate ventilation during laryngeal laser surgery in infants.


Assuntos
Ventilação em Jatos de Alta Frequência/métodos , Laringe/cirurgia , Terapia a Laser/métodos , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Estudos Retrospectivos
18.
Curr Treat Options Oncol ; 17(7): 37, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27262711

RESUMO

OPINION STATEMENT: The survival rate for patients with advanced stages of squamous cell carcinoma of the head and neck (SCCHN) remains poor despite multimodal treatment options. Cetuximab, an anti-EGFR inhibitor, is the only FDA-approved targeted agent for this disease. Recent findings have implicated modifications of the microenvironment and, consequently, phenotypical modifications of the cancer cell, in treatment resistance mechanisms. For many years, cancer research has focused mainly on targetable sites on or inside the cancer cell. Nowadays, in preclinical and clinical studies, a greater emphasis is being placed on drugs that target the tumor microenvironment. Potential targets relate to tumor vascularization, immunology, extracellular matrix components, or cancer-associated fibroblasts. The combination of these new agents with standard treatment options is of particular interest to overcome resistance mechanisms and/or to increase treatment efficacy. Whereas antiangiogenic agents show poor clinical activity, immunotherapy seems to be a more promising tool with an objective response rate (ORR) of 20 % in patients with recurrent and/or metastatic squamous cell carcinoma (R/M SCC). Other targets, located inside the extracellular matrix or on cancer associated fibroblasts, are under preclinical investigation. These new agents all need to be tested in clinical trials alone, or in combination with standard treatment modalities, based on preclinical data. To increase our knowledge of the complex network between the cancer cell and its environment, preclinical studies should consider co-culture models, and clinical studies should incorporate a translational research objective.


Assuntos
Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/etiologia , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Terapia de Alvo Molecular , Microambiente Tumoral , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/imunologia , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Progressão da Doença , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/genética , Matriz Extracelular/imunologia , Matriz Extracelular/metabolismo , Humanos , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
20.
Cell Mol Life Sci ; 73(13): 2491-509, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27007508

RESUMO

Since decades it has been known that non-protein-coding RNAs have important cellular functions. Deep sequencing recently facilitated the discovery of thousands of novel transcripts, now classified as long noncoding RNAs (lncRNAs), in many vertebrate and invertebrate species. LncRNAs are involved in a wide range of cellular mechanisms, from almost all aspects of gene expression to protein translation and stability. Recent findings implicate lncRNAs as key players of cellular differentiation, cell lineage choice, organogenesis and tissue homeostasis. Moreover, lncRNAs are involved in pathological conditions such as cancer and cardiovascular disease, and therefore provide novel biomarkers and pharmaceutical targets. Here we discuss examples illustrating the versatility of lncRNAs in gene control, development and differentiation, as well as in human disease.


Assuntos
Doenças Cardiovasculares/genética , Regulação da Expressão Gênica , Neoplasias/genética , RNA Longo não Codificante/genética , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Montagem e Desmontagem da Cromatina , Metilação de DNA , Epigênese Genética , Código das Histonas , Humanos , Neoplasias/metabolismo , Neoplasias/patologia , RNA Longo não Codificante/análise , RNA Longo não Codificante/metabolismo
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