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1.
Future Oncol ; 15(18): 2073-2082, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31094225

RESUMO

Bemarituzumab is an afucosylated monoclonal antibody against FGFR2b (a FGF receptor) with demonstrated monotherapy clinical activity in patients with late-line gastric cancer whose tumors overexpress FGFR2b (NCT02318329). We describe the rationale and design of the FIGHT trial (NCT03343301), a global, randomized, double-blind, placebo-controlled Phase III study evaluating the role of bemarituzumab in patients with previously untreated, FGFR2b-overexpressing advanced gastroesophageal cancer. Patients are randomized in a blinded fashion to the combination of mFOLFOX6 and bemarituzumab or mFOLFOX6 and placebo. Eligible patients are selected based on the presence of either FGFR2b protein overexpression determined by immunohistochemistry or FGFR2 gene amplification determined by circulating tumor DNA. The primary end point is overall survival, and secondary end points include progression-free survival, objective response rate and safety.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos Clínicos , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/genética , Junção Esofagogástrica/metabolismo , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/genética , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Bevacizumab/administração & dosagem , Biomarcadores Tumorais , Neoplasias Esofágicas/diagnóstico , Junção Esofagogástrica/patologia , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/uso terapêutico , Amplificação de Genes , Humanos , Leucovorina/efeitos adversos , Leucovorina/uso terapêutico , Masculino , Compostos Organoplatínicos/efeitos adversos , Compostos Organoplatínicos/uso terapêutico , Receptor Tipo 2 de Fator de Crescimento de Fibroblastos/metabolismo , Projetos de Pesquisa , Neoplasias Gástricas/diagnóstico
2.
Front Oncol ; 4: 179, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25161956

RESUMO

BACKGROUND: There is growing evidence that human immunodeficiency virus (HIV)-infected women might have a different human papillomavirus (HPV) type distribution in cervical dysplasia specimens as compared to the general population. This has implications for primary prevention. OBJECTIVE: We aimed to obtain preliminary data on the HPV genotypes prevalent in histological samples of HIV-infected women with cervical intraepithelial neoplasia (CIN) 3/CIS of the cervix in Miami, FL, USA. METHODS: Retrospective data were collected on HIV-infected women referred to the University of Miami-Jackson Memorial Hospital colposcopy clinic between years 2000 and 2008. The histology slides of CIN 3/CIS biopsies underwent pathological review and sections were cut from these archived specimens for HPV DNA extraction. HPV genotyping was then performed using the GeneSquare™ HPV genotyping assay. We report on our first set of 23 samples. RESULTS: Eight high-risk HPV types were detected. Types in decreasing order of frequency were 16, 35, 45, 52, 59, 31, 58, and 56. Most cases had multiple infections. HPV type 16 was the most common (45%) followed by HPV-35 and -45 with equal frequency (40%). No samples contained HPV-18. CONCLUSION: Our preliminary results suggest that cervical dysplasia specimens of HIV-infected women more likely (55%) contain non-16 and -18 high-risk HPV types. We show that this held true for histologically confirmed severe dysplasia and carcinoma-in situ. Epidemiological studies guide vaccine development, therefore HPV type prevalence in CIS and invasive cervical cancer among HIV-infected women should be more rigorously explored to ensure that this highly vulnerable population receives appropriate primary prevention.

3.
Gynecol Oncol ; 116(3): 572-7, 2010 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19906410

RESUMO

OBJECTIVE: To review and summarize evidence from clinical, translational and epidemiologic studies which have examined the clinically relevant aspects of HPV type prevalence and cervical dysplasia in HIV-infected women. METHODS: Relevant studies were identified through a MEDLINE search. References of identified reports were also used to identify additional published articles for review. RESULTS: HIV-infected women in different geographic regions (such as Zambia, Brazil, Rochester NY) appear to be infected with less prevalent types of HR-HPV as compared to the general population who, across all continents, are more commonly infected with types 16 and 18. Secondly, integration of HPV DNA into the host genome is no longer thought to be a necessary cause of malignant transformation of cervical cells. However, rate of integration appears to differ by the type of HPV. In fact, the types of HPV which appear to be more common in cervical dysplasia of HIV-infected women are the same types which are more likely to require integration for malignant transformation. Finally, HPV types found in HIV-infected women are relatively common and likely to persist. The most common among these types belong to the alpha-9 and -7 species which are the most carcinogenic species. CONCLUSION: Given that current vaccines target HR-HPV-16/18, the findings from the above mentioned studies may have important implications for the design of HPV vaccines that target the types of HPV associated with disease risk in HIV-infected women. HPV typing and assessment of the physical state (whether it is integrated or episomal) appear to be two valuable parameters for the prognostic evaluation of dysplastic lesions of the uterine cervix. This, however, has not yet been assessed in HIV-infected women. Recent data about the immune response in HPV/HIV co-infection may lead to understanding potential mechanisms for less virulent HPV causing malignant transformation in HIV-infected women.


Assuntos
Infecções por HIV/virologia , HIV/isolamento & purificação , Papillomavirus Humano 16/isolamento & purificação , Papillomavirus Humano 18/isolamento & purificação , Infecções por Papillomavirus/virologia , Displasia do Colo do Útero/virologia , Feminino , Genótipo , Infecções por HIV/epidemiologia , Papillomavirus Humano 16/genética , Papillomavirus Humano 18/genética , Humanos , Infecções por Papillomavirus/epidemiologia , Neoplasias do Colo do Útero/virologia
4.
J Immunol ; 171(4): 1780-91, 2003 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-12902478

RESUMO

Although differentiation of leukemic blasts to dendritic cells (DC) has promise in vaccine strategies, the mechanisms underlying this differentiation and the differences between leukemia and normal progenitor-derived DC are largely undescribed. In the case of chronic myeloid leukemia (CML), understanding the relationship between the induction of DC differentiation and the expression of the BCR-ABL oncogene has direct relevance to CML biology as well as the development of new therapeutic approaches. We now report that direct activation of protein kinase C (PKC) by the phorbol ester PMA in the BCR-ABL(+) CML cell line K562 and primary CML blasts induced nonterminal differentiation into cells with typical DC morphology (cytoplasmic dendrites), characteristic surface markers (MHC class I, MHC class II, CD86, CD40), chemokine and transcription factor expression, and ability to stimulate T cell proliferation (equivalent to normal monocyte-derived DC). PKC-induced differentiation was associated with down-regulation of BCR-ABL mRNA expression, protein levels, and kinase activity. This down-regulation appeared to be signaled through the mitogen-activated protein kinase pathway. Therefore, PKC-driven differentiation of CML blasts into DC-like cells suggests a potentially novel strategy to down-regulate BCR-ABL activity, yet raises the possibility that CML-derived DC vaccines will be less effective in presenting leukemia-specific Ags.


Assuntos
Crise Blástica/patologia , Células Dendríticas/patologia , Regulação para Baixo/genética , Proteínas de Fusão bcr-abl/genética , Genes abl , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Proteínas Tirosina Quinases , Proteínas Proto-Oncogênicas/genética , Crise Blástica/genética , Crise Blástica/imunologia , Cálcio/metabolismo , Cálcio/fisiologia , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Divisão Celular/efeitos dos fármacos , Divisão Celular/imunologia , Linhagem da Célula/genética , Linhagem da Célula/imunologia , Células Cultivadas , Citocinas/farmacologia , Células Dendríticas/enzimologia , Ativação Enzimática/efeitos dos fármacos , Ativação Enzimática/genética , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/biossíntese , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/imunologia , Genes abl/imunologia , Humanos , Líquido Intracelular/metabolismo , Células K562 , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Proteína Quinase C/metabolismo , Proteína Quinase C/fisiologia , Proteínas Proto-Oncogênicas/antagonistas & inibidores , Proteínas Proto-Oncogênicas/biossíntese , Proteínas Proto-Oncogênicas c-bcr , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Acetato de Tetradecanoilforbol/farmacologia , Células Tumorais Cultivadas , Fator de Necrose Tumoral alfa/farmacologia
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