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Gene Ther ; 27(3-4): 182, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32111977


An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Ann Oncol ; 27(12): 2210-2215, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27681866


BACKGROUND: Treatment with sorafenib, although associated with inhibition of tumour growth and angiogenesis in in vivo studies, leads to up-regulation of pERK. The addition of MEK inhibition could potentially abrogate this effect and potentiate anti-tumour activity. This phase I study investigated the maximum tolerated dose (MTD), safety, tolerability, pharmacokinetics (PK) and biomarker correlates of selumetinib combined with sorafenib in patients with advanced hepatocellular carcinoma (HCC). METHODS: Patients with Child-Pugh (CP) score ≤7 were treated with 400 mg twice daily of sorafenib with escalating doses of selumetinib in a 3 + 3 study design. The dose-limiting toxicity (DLT) evaluation period was 28 days. PK of selumetinib was determined. Angiogenic effect was evaluated with dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). RESULTS: Twenty-seven patients of Asian ethnicity were enrolled. The MTD was selumetinib 75 mg daily with sorafenib 400 mg twice daily. DLT included grade 3 transaminitis, diarrhoea and fatigue. Most common treatment-related adverse events at MTD (all grades) were diarrhoea (85%), rash (59%), hypertension (44%), fatigue (30%), anorexia (22%) and hand-foot syndrome (22%). Four patients (15%) had PR and 13 (48%) had SD. PR or SD was observed for ≥6 months in seven patients. The median overall survival was 14.4 months. Selumetinib exposures in combination with sorafenib were comparable to other monotherapy studies. A reduction in permeability-surface area product noted in DCE-MRI with treatment correlated with worse survival outcomes. CONCLUSION: The MTD of selumetinib was 75 mg daily when combined with sorafenib 400 mg twice a day in CP ≤7 HCC. Acceptable adverse events and encouraging anti-tumour activity warrant further evaluation. DCE-MRI findings deserve prospective evaluation. CLINICALTRIALSGOV IDENTIFIER: NCT01029418.

Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Benzimidazóis/administração & dosagem , Carcinoma Hepatocelular/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Niacinamida/análogos & derivados , Compostos de Fenilureia/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Benzimidazóis/efeitos adversos , Carcinoma Hepatocelular/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Neoplasias Hepáticas/patologia , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Niacinamida/administração & dosagem , Niacinamida/efeitos adversos , Compostos de Fenilureia/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Sorafenibe
Br J Cancer ; 111(11): 2067-75, 2014 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-25247318


BACKGROUND: This phase II, open-label, randomised study evaluated whether patients with metastatic pancreatic cancer receiving erlotinib/gemcitabine derived survival benefits from increasing the erlotinib dose. METHODS: After a 4-week run-in period (gemcitabine 1000 mg m(-2) once weekly plus erlotinib 100 mg per day), patients with metastatic pancreatic cancer who developed grade 0/1 rash were randomised to receive gemcitabine plus erlotinib dose escalation (150 mg, increasing by 50 mg every 2 weeks (maximum 250 mg); n=71) or gemcitabine plus standard-dose erlotinib (100 mg per day; n=75). The primary end point was to determine whether overall survival (OS) was improved by increasing the erlotinib dose. Secondary end points included progression-free survival (PFS), incidence of grade ⩾2 rash, and safety. RESULTS: Erlotinib dose escalation induced grade ⩾2 rash in 29 out of 71 (41.4%) patients compared with 7 out of 75 (9.3%) patients on standard dose. Efficacy was not significantly different in the dose-escalation arm compared with the standard-dose arm (OS: median 7.0 vs 8.4 months, respectively, hazard ratio (HR), 1.26, 95% confidence interval (CI): 0.88-1.80; P=0.2026; PFS: median 3.5 vs 4.5 months, respectively, HR, 1.09, 95% CI: 0.77-1.54; P=0.6298). Incidence of adverse events was comparable between randomised arms. CONCLUSION: The erlotinib dose-escalation strategy induced rash in some patients; there was no evidence that the higher dose translated into increased benefit.

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Exantema/induzido quimicamente , Neoplasias Pancreáticas/tratamento farmacológico , Quinazolinas/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Receptores ErbB/antagonistas & inibidores , Cloridrato de Erlotinib , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Quinazolinas/efeitos adversos
Eur J Surg Oncol ; 40(8): 909-16, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24768445


BACKGROUND: An increasing number of patients are presenting with peritoneal carcinomatosis and more centers are performing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). While morbidity and mortality are shown to be acceptable, quality of life after surgery should be assessed. METHODS: 63 patients who had CRS and HIPEC from 2001 to 2012 and who were still alive and on follow up were included. The EORTC-QLQ-C30 was administered to the patients. RESULTS: Median age was 53 years (14-71). 44% had ovarian primaries, 21% had appendicael primaries and 19% had colorectal primaries. Median follow-up was 1.08 years (0.06-9.8). The median time from surgery to the questionnaire was 1.3 years (0.24-10.18). There was no statistical difference in scores when comparing by age, gender, recurrence, gender, PCI score, presence of a complication and type of primary cancer. Scores were highest less than 6 months after surgery, dropped subsequently but rose again after 2 years. Our patients had better scores compared to a control group of outpatient cancer patients at our institution as well as the reference EORTC group. CONCLUSIONS: In keeping with previous quality of life studies done for CRS and HIPEC patients, we have shown that our patients can achieve a good quality of life after CRS and HIPEC even with recurrent disease.

Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimioterapia do Câncer por Perfusão Regional , Hipertermia Induzida , Neoplasias Peritoneais/secundário , Neoplasias Peritoneais/terapia , Qualidade de Vida , Adolescente , Adulto , Idoso , Neoplasias do Apêndice/patologia , Quimioterapia Adjuvante , Quimioterapia do Câncer por Perfusão Regional/métodos , China/etnologia , Neoplasias Colorretais/patologia , Intervalo Livre de Doença , Feminino , Seguimentos , Nível de Saúde , Humanos , Índia/etnologia , Masculino , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Cavidade Peritoneal , Neoplasias Peritoneais/tratamento farmacológico , Neoplasias Peritoneais/mortalidade , Neoplasias Peritoneais/cirurgia , Papel (figurativo) , Singapura , Inquéritos e Questionários , Resultado do Tratamento
Gene Ther ; 19(2): 189-200, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-21633393


Tumor-tropic neural stem cells (NSCs) can be used in the Trojan horse approach as cellular vehicles for targeted delivery of therapeutic agents to distant tumor sites. To realize this cancer therapy potential, it is important to have a renewable source to generate large quantities of uniform human NSCs. Here, we reported that NSCs derived from HES1 human embryonic stem cell line were capable of migrating into intracranial glioma xenografts after systemic injection or after intracranial injection at a site distant from the tumor. To test whether the HES1-derived NSCs can be used for cancer gene therapy, we used a baculoviral vector to introduce the herpes simplex virus thymidine kinase suicide gene into the cells and demonstrated that baculovirus-mediated transgene expression may last for at least 3 weeks in NSCs. After being injected into the cerebral hemisphere opposite the tumor site and in the presence of ganciclovir, NSCs expressing the suicide gene were able to inhibit the growth of human glioma xenografts and prolong survival of tumor-bearing mice. Our findings suggest that human embryonic stem cells could potentially serve as a clinically viable source for production of cellular vehicles suitable for targeted anticancer gene therapy.

Genes Transgênicos Suicidas/genética , Terapia Genética , Glioma/terapia , Timidina Quinase/genética , Animais , Baculoviridae/genética , Células-Tronco Embrionárias/metabolismo , Ganciclovir/farmacologia , Regulação Neoplásica da Expressão Gênica , Genes Transgênicos Suicidas/efeitos dos fármacos , Vetores Genéticos/administração & dosagem , Glioma/genética , Glioma/patologia , Humanos , Injeções , Camundongos , Células-Tronco Neurais/metabolismo , Simplexvirus/genética , Timidina Quinase/administração & dosagem , Transplante Heterólogo
J Bioinform Comput Biol ; 1(3): 521-39, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-15290768


This paper presents a novel approach for complex disease prediction that we have developed, exemplified by a study on risk of coronary artery disease (CAD). This multi-disciplinary approach straddles fields of microarray technology and genetics, neural networks (NN), data mining and machine learning, as well as traditional statistical analysis techniques, namely principal components analysis (PCA) and factor analysis (FA). A description of the biological background of the study is given, followed by a detailed description of how the problem has been modeled for analyses by neural networks and FA. A committee learning approach for NN has been used to improve generalization rates. We show that our NN approach is able to yield promising prediction results despite using only the most fundamental network structures. More interestingly, through the statistical analysis process, genes of similar biological functions have been clustered. In addition, a gene marker involved in breaking down lipids has been found to be the most correlated to CAD.

Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/genética , Análise de Sequência com Séries de Oligonucleotídeos/estatística & dados numéricos , Algoritmos , Inteligência Artificial , Biologia Computacional , Doença da Artéria Coronariana/sangue , Bases de Dados Genéticas , Análise Fatorial , Genótipo , Humanos , Lipídeos/sangue , Análise de Componente Principal , Fatores de Risco