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1.
Head Neck ; 2020 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-32583557

RESUMO

BACKGROUND: The present study evaluated the 2-year survival of the Asian population in the CheckMate 141 trial. METHODS: The CheckMate 141 trial included patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN). In the present study, 34 Asian patients (nivolumab group: 23 patients; investigator's choice of therapy [IC] group: 11 patients) were analyzed. RESULTS: The median overall survival (OS) was 12.1 and 6.2 months for the nivolumab and IC groups, respectively. The estimated 2-year OS rates were 22.7% and 0% for the nivolumab and IC groups, respectively. In the nivolumab group, the patients with any treatment-related adverse events (TRAEs), including skin-related disorders, showed better OS than the patients without any TRAEs. CONCLUSIONS: Nivolumab demonstrated prolonged OS benefits in the Asian population with platinum-refractory R/M SCCHN and a favorable safety profile. TRAEs, including skin-related disorders, may be favorable prognostic factors for nivolumab efficacy. CLINICAL TRIAL REGISTRATION: NCT02105636.

2.
J Formos Med Assoc ; 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31902466

RESUMO

BACKGROUND: For locally advanced head and neck cancers, intra-arterial (IA) chemotherapy is utilized for locoregional control with favorable results. The study aimed to evaluate the surgical outcomes of microsurgical reconstruction in head and neck cancer patients with IA chemotherapy METHODS: This cohort study retrospectively reviewed patients who underwent head and neck microsurgical reconstruction from January 2014 to August 2018. Patients with prior history of chemotherapy were included and categorized into two groups according to history of IA chemotherapy (IA group)/intravenous chemotherapy (IV group). Flap survival was evaluated along with microsurgical revision rates and complications. Recipient vessel specimens were analyzed by histological examination. A 1:1 propensity score matched analysis was performed. RESULTS: The study cohort included 45 patients with IA chemotherapy and 201 patients with IV chemotherapy. After propensity score matching, the difference in total flap loss and microsurgical revision rates were nonsignificant between two groups. However, the IA group had significantly higher rates of arterial thrombosis (Odds ratio [OR] 4.98; 95%CI, 1.28-19.38; p = 0.021), wound-related complications (OR 3.30; 95%CI, 1.21-9.02; p = 0.02) and revision surgery within one month (OR 3.73; 95%CI, 1.10-12.64; p = 0.035). Based on histology, IA group vessels showed a higher intima/media ratio than the IV group (0.45 ± 0.06 versus 0.23 ± 0.03, p = 0.02) CONCLUSION: Despite treating local advanced head and neck cancers with good results, IA chemotherapy may cause subsequent deleterious effects on local tissue due to the high concentration of cytotoxic chemotherapeutic agents. Surgeons should be cautious in selection of recipient vessels when performing microvascular reconstruction.

3.
Lancet ; 394(10212): 1915-1928, 2019 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-31679945

RESUMO

BACKGROUND: Pembrolizumab is active in head and neck squamous cell carcinoma (HNSCC), with programmed cell death ligand 1 (PD-L1) expression associated with improved response. METHODS: KEYNOTE-048 was a randomised, phase 3 study of participants with untreated locally incurable recurrent or metastatic HNSCC done at 200 sites in 37 countries. Participants were stratified by PD-L1 expression, p16 status, and performance status and randomly allocated (1:1:1) to pembrolizumab alone, pembrolizumab plus a platinum and 5-fluorouracil (pembrolizumab with chemotherapy), or cetuximab plus a platinum and 5-fluorouracil (cetuximab with chemotherapy). Investigators and participants were aware of treatment assignment. Investigators, participants, and representatives of the sponsor were masked to the PD-L1 combined positive score (CPS) results; PD-L1 positivity was not required for study entry. The primary endpoints were overall survival (time from randomisation to death from any cause) and progression-free survival (time from randomisation to radiographically confirmed disease progression or death from any cause, whichever came first) in the intention-to-treat population (all participants randomly allocated to a treatment group). There were 14 primary hypotheses: superiority of pembrolizumab alone and of pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival and progression-free survival in the PD-L1 CPS of 20 or more, CPS of 1 or more, and total populations and non-inferiority (non-inferiority margin: 1·2) of pembrolizumab alone and pembrolizumab with chemotherapy versus cetuximab with chemotherapy for overall survival in the total population. The definitive findings for each hypothesis were obtained when statistical testing was completed for that hypothesis; this occurred at the second interim analysis for 11 hypotheses and at final analysis for three hypotheses. Safety was assessed in the as-treated population (all participants who received at least one dose of allocated treatment). This study is registered at ClinicalTrials.gov, number NCT02358031. FINDINGS: Between April 20, 2015, and Jan 17, 2017, 882 participants were allocated to receive pembrolizumab alone (n=301), pembrolizumab with chemotherapy (n=281), or cetuximab with chemotherapy (n=300); of these, 754 (85%) had CPS of 1 or more and 381 (43%) had CPS of 20 or more. At the second interim analysis, pembrolizumab alone improved overall survival versus cetuximab with chemotherapy in the CPS of 20 or more population (median 14·9 months vs 10·7 months, hazard ratio [HR] 0·61 [95% CI 0·45-0·83], p=0·0007) and CPS of 1 or more population (12·3 vs 10·3, 0·78 [0·64-0·96], p=0·0086) and was non-inferior in the total population (11·6 vs 10·7, 0·85 [0·71-1·03]). Pembrolizumab with chemotherapy improved overall survival versus cetuximab with chemotherapy in the total population (13·0 months vs 10·7 months, HR 0·77 [95% CI 0·63-0·93], p=0·0034) at the second interim analysis and in the CPS of 20 or more population (14·7 vs 11·0, 0·60 [0·45-0·82], p=0·0004) and CPS of 1 or more population (13·6 vs 10·4, 0·65 [0·53-0·80], p<0·0001) at final analysis. Neither pembrolizumab alone nor pembrolizumab with chemotherapy improved progression-free survival at the second interim analysis. At final analysis, grade 3 or worse all-cause adverse events occurred in 164 (55%) of 300 treated participants in the pembrolizumab alone group, 235 (85%) of 276 in the pembrolizumab with chemotherapy group, and 239 (83%) of 287 in the cetuximab with chemotherapy group. Adverse events led to death in 25 (8%) participants in the pembrolizumab alone group, 32 (12%) in the pembrolizumab with chemotherapy group, and 28 (10%) in the cetuximab with chemotherapy group. INTERPRETATION: Based on the observed efficacy and safety, pembrolizumab plus platinum and 5-fluorouracil is an appropriate first-line treatment for recurrent or metastatic HNSCC and pembrolizumab monotherapy is an appropriate first-line treatment for PD-L1-positive recurrent or metastatic HNSCC. FUNDING: Merck Sharp & Dohme.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Idoso , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Neoplasias de Cabeça e Pescoço/mortalidade , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
4.
Pharmaceutics ; 11(11)2019 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-31744218

RESUMO

Long-circulating PEG-modified liposome has been shown to improve pharmacokinetic properties and reduce systemic toxicity in cancer treatment. However, drug bioavailability from liposome remains a major challenge to the improvement of its therapeutic efficacy. Previously, we designed a PEGylated dual-effect liposome (named as PL-Dox-Ce6) with chlorin e6 incorporated in the lipid bilayer and Doxorubicin encapsulated in the interior. In this study, another dual-effect liposome with cisplatin encapsulated in the interior was further developed. The pharmacokinetics of these two dual-effect liposomes were studied in tumor-bearing mice. Based on the kinetic data of tumor and plasma, light irradiation was applied onto the tumors at different time points after drug administration to compare the therapeutic efficacy. We demonstrated that a single dose of the dual-effect liposomes combined with two doses of light irradiation can completely eradicate over 90% of the tumor in mice alone with significant survival rate and no toxicity. Thus, this study established a platform that utilizes the dual-effect liposome which combines photodynamic therapy and chemotherapy to improve the therapeutic outcomes of tumors.

5.
BMC Musculoskelet Disord ; 20(1): 408, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484514

RESUMO

BACKGROUND: Mesenchymal chondrosarcoma (MCS) is a rare malignant variant of chondrosarcoma with a high tendency of recurrence and metastasis. Intradural extramedullary spinal MCS is exceedingly rare and usually found in pediatric patients. Herein, we present an elderly patient with primary intradural extramedullary spinal MCS. Relevant literatures are reviewed to disclose characteristics of intradural extramedullary spinal MCS. CASE PRESENTATION: A 64-year-old female presented with urinary difficulty and tightness of upper back preceding progressive weakness of right lower extremity. Magnetic resonance imaging revealed an intradural extramedullary tumor at the level of 3rd thoracic vertebra. This patient underwent total tumor resection and then received adjuvant radiotherapy. Histopathological examination showed that the tumor composed of spindle and round cells with high nucleocytoplasmic ratio accompanied by scattered eosinophilic chondroid matrix. Along with immunohistochemical findings and the existence of HEY1-NCOA2 fusion transcript, the diagnosis of MCS was confirmed. Neurologic deficit recovered nearly completely after surgery. No evidence of local recurrence or distant metastasis was found 5 years after treatments. Including the current case, a total of 18 cases have been reported in the literature with only one case with local recurrence and one case of mortality. The current case was the eldest patient diagnosed with primary intraspinal MCS in the literature. CONCLUSIONS: MCS rarely appears in the intradural space of the spine. In contrast to classic MCS, treatment outcome of primary intradural extramedullary spinal MCS is usually excellent as total tumor resection is commonly achievable. Adjuvant radiotherapy may reduce local recurrence and chemotherapy may be associated with fewer recurrences especially for unresectable tumors.


Assuntos
Condrossarcoma Mesenquimal/diagnóstico , Dura-Máter/patologia , Neoplasias da Medula Espinal/diagnóstico , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Condrossarcoma Mesenquimal/genética , Condrossarcoma Mesenquimal/terapia , Dura-Máter/diagnóstico por imagem , Dura-Máter/cirurgia , Feminino , Humanos , Laminectomia , Imagem por Ressonância Magnética , Pessoa de Meia-Idade , Coativador 2 de Receptor Nuclear/genética , Radioterapia Adjuvante , Neoplasias da Medula Espinal/genética , Neoplasias da Medula Espinal/terapia , Fusão Vertebral , Resultado do Tratamento
6.
Anticancer Res ; 39(3): 1355-1364, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30842169

RESUMO

BACKGROUND: Adults with rhabdomyosarcoma (RMS) have a worse clinical outcome compared to pediatric cases. In the present study, the failure pattern and clinical outcome of adult patients with RMS who received multimodality treatment at our Institution was assessed. PATIENTS AND METHODS: Data were retrospectively recorded and analyzed from 20 adult patients, aged 19 years or more, who were treated for RMS at our Institution between 2004 and 2015. Disease-free (DFS) and overall (OS) survival after starting treatment were calculated using the Kaplan-Meier method. The relationship of these outcome measures with the following variables was then assessed: Primary site, tumor stage, lymph node involvement, histological subtype, radiotherapy (RT), and duration of chemotherapy. RESULTS: Sixteen patients had localized RMS, and four had metastatic disease. For the whole patient cohort, the 3-year DFS and OS rates were 20%, and 45%, respectively. Patients with alveolar histological subtype had a better 3-year OS than those with other subtypes (p=0.038). The median OS rates for those with localized and metastatic disease were 53.2 (95% confidence interval(CI)=14.7-91.8) months, and 21.7 (95% CI=0-45.7) months, respectively (p=0.047). In patients with localized RMS, those who received RT (n=13) had a better median DFS (24.6 versus 6.0 months, p=0.009) and OS (53.2 versus 11.4 months, p=0.009) than those who did not (n=3). For patients receiving RT, concurrent chemotherapy with vincristine and cyclophosphamide (n=11) was associated with better 3-year DFS (36.4% versus 0%, p<0.001) and OS (81.8% versus 0%, p<0.001) compared with RT alone (n=2). Administration of chemotherapy for more than 19 weeks significantly correlated with better 3-year DFS (44% versus 0%, p=0.001) and OS (53.3% versus 0%, p<0.001) in those with localized RMS. CONCLUSION: In addition to staging and histological subtype, our results indicate that concurrent chemoradiotherapy and longer duration of chemotherapy were associated with significantly improved DFS and OS in adult patients with localized RMS.


Assuntos
Rabdomiossarcoma/terapia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Terapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Rabdomiossarcoma/patologia , Análise de Sobrevida , Resultado do Tratamento , Adulto Jovem
7.
Cancer Immunol Res ; 6(12): 1511-1523, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30242021

RESUMO

We developed a screening assay in which luciferized ID8 expressing OVA was cocultured with transgenic CD8+ T cells specifically recognizing the model antigen in an H-2b-restricted manner. The assay was screened with a small-molecule library to identify compounds that inhibit or enhance T cell-mediated killing of tumor cells. Erlotinib, an EGFR inhibitor, was the top compound that enhanced T-cell killing of tumor cells. Subsequent experiments with erlotinib and additional EGFR inhibitors validated the screen results. EGFR inhibitors increased both basal and IFNγ-induced MHC class-I presentation, which enhanced recognition and lysis of tumor cell targets by CD8+ cytotoxic T lymphocytes. The ID8 cell line was also transduced to constitutively express Cas9, and a pooled CRISPR screen, utilizing the same target tumor cell/T-cell assay, identified single-guide (sg)RNAs targeting EGFR that sensitized tumor cells to T cell-mediated killing. Combination of PD-1 blockade with EGFR inhibition showed significant synergistic efficacy in a syngeneic model, further validating EGFR inhibitors as immunomodulatory agents that enhance checkpoint blockade. This assay can be screened in high-throughput with small-molecule libraries and genome-wide CRISPR/Cas9 libraries to identify both compounds and target genes, respectively, that enhance or inhibit T-cell recognition and killing of tumor cells. Retrospective analyses of squamous-cell head and neck cancer (SCCHN) patients treated with the combination of afatinib and pembrolizumab demonstrated a rate of clinical activity exceeding that of each single agent. Prospective clinical trials evaluating the combination of an EGFR inhibitor and PD-1 blockade should be conducted.


Assuntos
Ensaios de Seleção de Medicamentos Antitumorais/métodos , Receptores ErbB/antagonistas & inibidores , Ensaios de Triagem em Larga Escala/métodos , Inibidores de Proteínas Quinases/farmacologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Afatinib/administração & dosagem , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfócitos T CD8-Positivos , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Técnicas de Cocultura , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Humanos , Luciferases de Vaga-Lume/genética , Camundongos Endogâmicos C57BL , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Linfócitos T Citotóxicos/imunologia
8.
Am J Clin Oncol ; 2018 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-29462123

RESUMO

OBJECTIVES: Treatment options for patients with unresectable or metastatic salivary gland carcinoma (SGC) are limited. Safety and efficacy of pembrolizumab for SGC expressing programmed death ligand 1 (PD-L1) were explored. MATERIALS AND METHODS: A cohort of patients with advanced, PD-L1-positive SGC was enrolled in the nonrandomized, multicohort, phase Ib trial of pembrolizumab in patients with PD-L1-positive advanced solid tumors (KEYNOTE-028; NCT02054806). Key inclusion criteria included recurrent or metastatic disease, failure of prior systemic therapy, and PD-L1 expression on ≥1% of tumor or stroma cells (per a prototype immunohistochemistry assay). Patients received pembrolizumab 10 mg/kg every 2 weeks for ≥2 years or until confirmed disease progression or unacceptable toxicity. Primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 by investigator review. RESULTS: Twenty-six patients with PD-L1-positive SGC were enrolled and treated; median age was 57 years, 88% were men, and 74% had received prior therapy for recurrent/metastatic disease. Confirmed objective response rate after median follow-up of 20 months was 12% (95% confidence interval, 2%-30%), with 3 patients achieving partial response; there were no complete responses. Median duration of response was 4 months (range, 4 to 21 mo). Treatment-related adverse events occurred in 22 patients (85%), resulting in discontinuation in 2 patients and death in 1 (interstitial lung disease); those occurring in ≥15% of patients were diarrhea, decreased appetite, pruritus, and fatigue. CONCLUSIONS: Pembrolizumab demonstrated promising antitumor activity and a manageable safety profile in patients with advanced, PD-L1-positive SGC.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

10.
Oral Oncol ; 73: 138-146, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28939066

RESUMO

OBJECTIVES: To assess efficacy and safety of nivolumab versus investigator's choice of therapy (IC) in Asian patients with platinum-refractory recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN). MATERIALS AND METHODS: Thirty-four patients from Japan, Taiwan, Hong Kong, and Korea received nivolumab 3mg/kg (n=23) every 2weeks or IC (n=11), as part of a global trial (n=361), until intolerable toxicity or disease progression. The primary endpoint was overall survival (OS). RESULTS: Median OS was 9.5months (95% confidence interval [CI] 9.1-NR) with nivolumab and 6.2months (95% CI 2.6-NR) with IC. Seven (30.4%) patients receiving nivolumab and six (54.5%) receiving IC died. The hazard ratio (HR) for risk of death (nivolumab vs. IC) was 0.50 (95% CI 0.17-1.48). Median progression-free survival was 1.9months (95% CI 1.6-7.5) with nivolumab and 1.8months (95% CI 0.4-6.1) with IC (HR 0.57 [95% CI 0.25-1.33]). Objective response rates (complete+partial responses) were 26.1% (6/23 patients; 95% CI 10.2-48.4) for nivolumab and 0% (0/11 patients; 95% CI 0.0-28.5) for IC. Sixteen (69.6%) nivolumab-treated patients and 10 (90.9%) patients receiving IC had a treatment-related adverse event, most commonly decreased appetite (21.7%), pruritus, rash, and fatigue (17.4% each) with nivolumab, and nausea, stomatitis, and decreased appetite (27.3% each) with IC. CONCLUSION: Nivolumab demonstrated a survival advantage compared with conventional treatments in Asian patients with platinum-refractory recurrent or metastatic SCCHN, and was well tolerated. Clinical trial registration NCT02105636.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Recidiva Local de Neoplasia , Ásia/etnologia , Carcinoma de Células Escamosas/etnologia , Neoplasias de Cabeça e Pescoço/etnologia , Humanos , Nivolumabe , Carcinoma de Células Escamosas de Cabeça e Pescoço
11.
J Pain Symptom Manage ; 54(1): 35-45.e4, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28450219

RESUMO

CONTEXT/OBJECTIVE: Temporal changes have not been examined in patient-caregiver agreement on life-sustaining treatment (LST) preferences at end of life (EOL). We explored the extent of and changes in patient-caregiver agreement on LST-preference patterns for two independent cohorts of Taiwanese cancer patient-family caregiver dyads recruited a decade apart. METHODS: We surveyed preferences for cardiopulmonary resuscitation, intensive care unit care, cardiac massage, intubation with mechanical ventilation, intravenous nutritional support, tube feeding, and dialysis among 1049 and 1901 dyads in 2003-2004 and 2011-2012, respectively. LST-preference patterns were examined by multi-group latent class analysis. Extent of patient-caregiver agreement on LST-preference patterns was determined by percentage agreement and kappa coefficients. RESULTS: For both patients and family caregivers, we identified seven distinct LST-preference classes. Patient-caregiver agreement on LST-preference patterns was poor to fair across both study cohorts, indicated by 24.4%-43.5% agreement and kappa values of 0.06 (95% CI: 0.04, 0.09) to 0.27 (0.23, 0.30), and declined significantly over time. Agreement on LST-preference patterns was most likely when both patients and caregivers uniformly rejected LSTs. When patients disagreed with caregivers on LST-preference patterns, discrepancies were most likely when patients totally rejected LSTs but caregivers uniformly preferred LSTs or preferred nutritional support but rejected other treatments. CONCLUSION: Patients and family caregivers had poor-to-fair agreement on LST-preference patterns, and agreement declined significantly over a decade. Encouraging an open dialogue between patients and their family caregivers about desired EOL care would facilitate patient-caregiver agreement on LST-preference patterns, thus honoring terminally ill cancer patients' wishes when they cannot make EOL-care decisions.


Assuntos
Cuidadores/psicologia , Família/psicologia , Cuidados para Prolongar a Vida/psicologia , Neoplasias/terapia , Assistência Terminal/psicologia , Doente Terminal , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Atitude Frente a Saúde , Estudos de Coortes , Estudos Transversais , Tomada de Decisões , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Procurador/psicologia , Taiwan , Doente Terminal/psicologia , Fatores de Tempo , Adulto Jovem
12.
Mol Cancer Ther ; 16(7): 1421-1434, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28265008

RESUMO

Transient chemotherapeutic response is a major obstacle to treating head and neck squamous cell carcinomas (HNSCC). Histone methyltransferase G9a has recently been shown to be abundantly expressed in HNSCC, and is required to maintain the malignant phenotype. In this study, we found that high G9a expression is significantly associated with poor chemotherapeutic response and disease-free survival in HNSCC patients. Similarly, G9a expression and enzymatic activity were elevated in cisplatin-resistant HNSCC cells. Genetic or pharmacologic inhibition of G9a sensitized the resistant cells to cisplatin, increasing cellular apoptosis. Mechanistic investigations indicated that G9a contributes to transcriptional activation of the glutamate-cysteine ligase catalytic subunit (GCLC), which results in upregulation of cellular glutathione (GSH) and drug resistance. In addition, we observed a significant positive correlation between G9a and GCLC expression in tumors of HNSCC patients. Taken together, our findings provide evidence that G9a protects HNSCC cells against chemotherapy by increasing the synthesis of GSH, and imply G9a as a promising target for overcoming cisplatin resistance in HNSCC. Mol Cancer Ther; 16(7); 1421-34. ©2017 AACR.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Glutamato-Cisteína Ligase/genética , Glutationa/genética , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Antígenos de Histocompatibilidade/genética , Histona-Lisina N-Metiltransferase/genética , Adulto , Idoso , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Cisplatino/administração & dosagem , Intervalo Livre de Doença , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glutationa/metabolismo , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Histona-Lisina N-Metiltransferase/antagonistas & inibidores , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ensaios Antitumorais Modelo de Xenoenxerto
13.
J Radiat Res ; 58(1): 114-122, 2017 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-27534792

RESUMO

Treatment strategies for nasal extranodal NK/T-cell lymphoma (ENKTL), including sequential chemotherapy followed by radiotherapy (SCRT), concurrent chemoradiotherapy (CCRT), or radiotherapy alone (RT), remain varied. The purpose of this study was to assess the treatment outcome, the toxicity, and the potential prognostic factors for patients with early-stage nasal ENKTL treated using definitive RT (minimum of 50 Gy) with or without chemotherapy. From 1998 to 2014, 37 patients were included in the study. Eight patients were treated with RT alone, 1 with CCRT, and 28 with SCRT. Local regional control (LRC), progression-free survival (PFS), and overall survival (OS) were calculated using the Kaplan-Meier method. RT resulted in an overall response rate of 91.2%, with a complete response rate of 78.4%. After a median follow-up time of 36.8 months, the 3-year LRC, PFS and OS were 87.4%, 64.0% and 76.3%, respectively. Acute severe toxicity (Grade 3) of mucositis was observed in 6 (16.2%) of the 37 patients. In univariate analyses, extensive disease (Stage I/II with local invasiveness) and the presence of B symptoms were significantly associated with a poor PFS, whereas extensive disease was significantly associated with a poor OS. Multivariate analysis identified the presence of extensive disease as an independent predictor of PFS (P < 0.001) and OS (P = 0.015). High-dose RT with or without chemotherapy reported promising locoregional control and a favorable outcome for patients with early-stage nasal ENKTL without local invasiveness. Further investigation of new treatment strategies for patients with local invasiveness is warranted.


Assuntos
Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/radioterapia , Intervalo Livre de Doença , Feminino , Humanos , Linfoma Extranodal de Células T-NK/patologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Resultado do Tratamento
14.
Oncotarget ; 8(8): 14068-14077, 2017 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-27764778

RESUMO

PURPOSE: To examine the survival outcomes and late toxicity profiles of three-dimensional conformal radiation therapy (3DCRT) vs. intensity-modulated radiation therapy (IMRT) for patients with nasopharyngeal carcinoma (NPC). METHODS: Three hundred and seventy-four patients with newly diagnosed, non-metastatic, NPC who were curatively treated with 3DCRT between 2004 and 2006 and 481 patients treated with IMRT between 2007 and 2009 were analyzed. Patients were categorized as having advanced-stage disease (stage III, IVA, and IVB disease; n = 709) or early-stage disease (stage I and II; n = 146). The median follow-up time was 90.3 months for patients treated with 3DCRT and 86.3 months for patients treated with IMRT. RESULTS: For early-stage patients, the outcomes of IMRT vs. 3DCRT were similar considering locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). For advanced-stage patients, IMRT was associated with better LRC compared with 3DCRT (5-year LRC rate: 85.6% vs. 76.6%, respectively; p = 0.035) and OS (5-year OS rate: 82.3% vs. 71.8%, respectively; p = 0.002), whereas DMFS was similar for both treatments (5-year DMFS rate: 80.9% vs. 79.0%, respectively; p = 0.324). Furthermore, the IMRT technique was more beneficial for patients with T4 disease. Late toxicities occurred more frequently in patients treated with 3DCRT than in those treated with IMRT (grade ≥3 neck fibrosis: 6.7% vs. 3.7%, respectively, p = 0.036; radiographic temporal lobe necrosis: 10.2% vs. 4.4%, respectively, p < 0.001). CONCLUSIONS: Compared with 3DCRT, IMRT offered better LRC in patients with advanced-stage non-metastatic NPC, which corresponded with better OS.


Assuntos
Carcinoma/radioterapia , Neoplasias Nasofaríngeas/radioterapia , Radioterapia Conformacional/efeitos adversos , Radioterapia de Intensidade Modulada , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma/mortalidade , Carcinoma/patologia , Criança , Intervalo Livre de Doença , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Radioterapia de Intensidade Modulada/efeitos adversos , Resultado do Tratamento , Adulto Jovem
15.
Sci Transl Med ; 7(290): 290ra91, 2015 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-26041708

RESUMO

Colorectal cancer is one of the most commonly diagnosed cancers and a leading cause of cancer mortality worldwide. Current treatment for colorectal cancer results in only limited success, and more effective therapeutic approaches are thus urgently needed. The development of new methods for early detection and effective treatments for cancer is contingent on the identification of biomarkers on the surface of cancer cells, as well as isolation of tumor-specific ligands with high binding affinity to such biomarkers. In vitro biopanning of a phage-displayed peptide library was used to identify specific peptides binding to human colorectal carcinoma cells. The targeting peptide pHCT74 showed the greatest potential for drug delivery in both in vitro and in vivo studies. The use of biotinylated peptides combined with an affinity trapping method and liquid chromatography-tandem mass spectrometry identified the target protein for the pHCT74 peptide as α-enolase. In animal model studies, combined pHCT74-conjugated liposomal doxorubicin (pHCT74-LD) and pHCT74-conjugated liposomal vinorelbine (pHCT74-sLV) therapy exhibited an enhanced antitumor effect and markedly extended the survival of mice with human colorectal cancer in subcutaneous and orthotopic models. Our findings indicate that α-enolase-targeted lipid nanoparticles have great potential for application in targeted drug delivery systems for colorectal cancer therapy.


Assuntos
Neoplasias Colorretais/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Peptídeos/uso terapêutico , Fosfopiruvato Hidratase/metabolismo , Sequência de Aminoácidos , Humanos , Dados de Sequência Molecular , Peptídeos/química , Peptídeos/metabolismo , Peptídeos/farmacologia , Homologia de Sequência de Aminoácidos , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
16.
Lasers Surg Med ; 47(1): 77-87, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25559348

RESUMO

BACKGROUND AND OBJECTIVE: Long circulating doxorubicin (Dox)-loaded PEGylated liposomes are clinically safer than the free form due to the significant reduction of cardiac toxicity. However, the therapeutic efficacy of the PEGylated liposome could further be improved if poor diffusivity and slow drug release of the liposome in tumor interstitium can be overcome. In this study, a dual-effect liposome triggered by photodynamic effect was developed to improve the therapeutic efficacy of Dox-loaded PEGylated liposomes. MATERIALS AND METHODS: Dox and chlorin e6 (Ce6) were co-encapsulated in PEGylated liposomes (named as PL-Dox-Ce6). To induce the drug release, photodynamic effect was triggered by the light irradiation of a 662 nm diode laser. The cellular distribution of Dox and Ce6 was examined under confocal microscope. The in vitro and in vivo cytotoxicity of PL-Dox-Ce6 was determined via the colony formation assay and the synergistic C26 tumor model, respectively. RESULTS: The cellular distribution of PL-Dox-Ce6 was in the cytoplasmic area; while under light irradiation, Dox was co-localized with nuclear staining positive signals. The cellular cytotoxicity of PL-Dox-Ce6 was significantly higher than the controls including liposomes encapsulating either Dox (PL-Dox) or Ce6 (PL-Ce6). The in vivo treatment efficacy of PL-Dox-Ce6 determined in the C26 tumor model reveals a significant therapeutic effect compared to that of PL-Ce6 and PL-Dox alone or in combination. CONCLUSION: This study indicates that this dual-effect PEGylated liposome could provide clinical advantages in the combination regimen of photodynamic therapy and chemotherapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias do Colo/tratamento farmacológico , Lasers Semicondutores/uso terapêutico , Fotoquimioterapia/métodos , Animais , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Humanos , Lipossomos , Masculino , Melanoma/tratamento farmacológico , Camundongos , Camundongos Endogâmicos BALB C , Células-Tronco Neoplásicas/efeitos dos fármacos , Fármacos Fotossensibilizantes/administração & dosagem , Polietilenoglicóis/administração & dosagem , Porfirinas/administração & dosagem , Distribuição Aleatória , Ensaio Tumoral de Célula-Tronco , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Cancer Med ; 2(3): 351-9, 2013 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-23930212

RESUMO

TAS-106, a RNA polymerase inhibitor, was studied in solid tumors with potential clinical benefit and reasonable tolerability. We conducted a multicenter, international phase II trial of TAS-106 in salvage metastatic or recurrent head and neck squamous cell cancer (HNSCC) and nasopharyngeal cancer (NPC) patients. TAS-106 monotherapy was given at 6.5 mg/m(2) over 24-h continuous infusion every 3 weeks. Translational studies for blood and tissue were included. Twenty-seven enrolled patients experienced the most common drug-related adverse events of neutropenia, fatigue, non-neutropenic fever, injection site reaction, and skin rash/dermatitis. The greater than or equal to grade 3 adverse events included neutropenia (14.8%), febrile neutropenia (7.4%), pneumonia (7.4%), and peripheral neuropathy (3.7%). The overall response rate was 0% in both subgroups; five HNSCC patients had stable disease (median duration 99 days) and four NPC patients had stable disease (median duration of 92.5 days). Median progression-free survival (PFS) for HNSCC patients was 52 days (95% CI 43.0-99.0 days) and 48 days (95% CI 41.0-83.0 days) for NPC. Median overall survival (OS) for HNSCC patients was 175 days (95% CI 92.0-234.0 days) and 280 days (95% CI 107.0-462.0 days) for NPC. The TAS-106 plasma levels were equivalent between Asian and Caucasian patients. There was no significant correlation of tumor UCK2 protein expression levels to TAS-106 efficacy. TAS-106 was reasonably tolerated in patients with platinum-failure HNSCC and NPC. The administration schedule of 24-h continuous infusion prevented neurologic toxicity, but had myelosuppression as its main toxicity. There was no anti-tumor efficacy seen with TAS-106 monotherapy. Future studies will focus on TAS-106 combinations and mechanisms of drug resistance.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Citidina/análogos & derivados , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias Nasofaríngeas/tratamento farmacológico , Idoso , Carcinoma , Citidina/efeitos adversos , Citidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Carcinoma Nasofaríngeo , Metástase Neoplásica , Recidiva Local de Neoplasia/tratamento farmacológico , Terapia de Salvação , Carcinoma de Células Escamosas de Cabeça e Pescoço , Taxa de Sobrevida
18.
Lung Cancer ; 81(1): 27-31, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23639785

RESUMO

Thymic tumors are epithelial tumors of the thymus for which multimodal therapies are often ineffective because of a lack of standardized regimens. Due to the low incidence, the molecular pathology and genomic abnormalities of thymic epithelial tumors are largely unknown. In this study, we report our comprehensively genomic study on a case of metastatic thymic tumor. Using next generation deep DNA sequencing technology, we sequenced 190 segments of 46 cancer genes of the cancer genome to cover 739 COSMIC mutations in 604 loci. Among these sequenced cancer genes, we identified that three low frequency (~10% of cells) mutations in the TP53 gene (c.782+1G>T), ALK gene (c.3551C>T), and RET gene (c.2651A>T). To the best of our knowledge, this is the first study to show those mutations in thymic tumor. Of note, our study further indicates comprehensive molecular analysis may facilitate development of novel diagnostic and therapeutic strategies for thymic tumors.


Assuntos
Carcinoma de Células Escamosas/genética , Genes p53 , Mutação , Proteínas Proto-Oncogênicas c-ret/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias do Timo/genética , Adulto , Quinase do Linfoma Anaplásico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Cisplatino/uso terapêutico , Humanos , Masculino , Neoplasias do Timo/tratamento farmacológico , Neoplasias do Timo/patologia
19.
Clin Cancer Res ; 19(8): 2208-15, 2013 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-23459720

RESUMO

PURPOSE: Persistently elevated posttreatment plasma EBV DNA is a robust predictor of relapse in nasopharyngeal carcinoma (NPC). However, assay standardization is necessary for use in biomarker-driven trials. We conducted a study to harmonize the method between four centers with expertise in EBV DNA quantitation. EXPERIMENTAL DESIGN: Plasma samples of 40 patients with NPC were distributed to four centers. DNA was extracted and EBV DNA copy number was determined by real-time quantitative PCR (BamHI-W primer/probe). Centers used the same protocol but generated their own calibrators. A harmonization study was then conducted using the same calibrators and PCR master mix and validated with ten pooled samples. RESULTS: The initial intraclass correlations (ICC) for the first 40 samples between each center and the index center were 0.62 [95% confidence interval (CI): 0.39-0.78], 0.70 (0.50-0.83), and 0.59 (0.35-0.76). The largest variability was the use of different PCR master mixes and calibrators. Standardization improved ICC to 0.83 (0.5-0.95), 0.95 (0.83-0.99) and 0.96 (0.86-0.99), respectively, for ten archival frozen samples. For fresh plasma with spiked-in EBV DNA, correlations were more than 0.99 between the centers. At 5 EBV DNA copies per reaction or above, the coefficient of variance (CV) was less than 10% for the cycle threshold (Ct) among all centers, suggesting this concentration can be reliably used as a cutoff for defining the presence of detectable EBV DNA. CONCLUSIONS: Quantitative PCR assays, even when conducted in experienced clinical labs, can yield large variability in plasma EBV DNA copy numbers without harmonization. The use of common calibrators and PCR master mix can help to reduce variability.


Assuntos
DNA Viral/sangue , Infecções por Vírus Epstein-Barr/virologia , Herpesvirus Humano 4/genética , Neoplasias Nasofaríngeas/virologia , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/normas , Calibragem/normas , Carcinoma , DNA Viral/genética , DNA Viral/normas , Infecções por Vírus Epstein-Barr/sangue , Infecções por Vírus Epstein-Barr/diagnóstico , Humanos , Cooperação Internacional , Laboratórios/normas , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas/sangue , Reação em Cadeia da Polimerase em Tempo Real/métodos , Reação em Cadeia da Polimerase em Tempo Real/normas , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
20.
Asia Pac J Clin Oncol ; 9(4): 331-41, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23442047

RESUMO

AIM: An exploratory subgroup analysis of East Asian (EA) patients in a phase III trial was conducted to assess efficacy and safety trends based on ethnicity. METHODS: The 795 patients with recurrent or metastatic squamous cell carcinoma of the head and neck included 111 EA patients randomized to pemetrexed-cisplatin (n = 55) and placebo-cisplatin (n = 56) and 684 non- EA patients randomized to pemetrexed-cisplatin (n = 343) and placebo-cisplatin (n = 341). Treatment differences in median overall survival and progression-free survival were compared using a stratified log-rank test. Survival was estimated using the Kaplan-Meier method. RESULTS: The median overall survival in the pemetrexed-cisplatin and placebo-cisplatin arms of the EA group (6.8 and 5.7 months, respectively [P = 0.275]) was similar to that in the global population (7.3 and 6.3 months, respectively [P = 0.082]); the median progression-free survival in the pemetrexed-cisplatin and placebo-cisplatin arms in the EA group (2.8 and 1.9 months, respectively [P = 0.748]) was similar to that in the global population (3.6 and 2.8 months, respectively [P = 0.166]). Compared to the findings in the global population, overall survival for the EA group receiving prior platinum-based therapy was longer (P = 0.042 vs P = 0.065). There was no significant interaction between treatment arms and ethnicity. CONCLUSION: Consistent with findings in the global population, pemetrexed-cisplatin did not improve survival compared with placebo-cisplatin for the EA group. However, in a subgroup analysis, pemetrexed-cisplatin showed an overall survival advantage in EA patients receiving prior platinum-based therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/etnologia , Cisplatino/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/etnologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Grupo com Ancestrais do Continente Asiático , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Método Duplo-Cego , Feminino , Glutamatos/administração & dosagem , Glutamatos/efeitos adversos , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/análogos & derivados , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/etnologia , Pemetrexede , Carcinoma de Células Escamosas de Cabeça e Pescoço , Análise de Sobrevida , Resultado do Tratamento
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