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1.
Recent Results Cancer Res ; 214: 1-70, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473848

RESUMO

Exploiting the unique specificity of monoclonal antibodies has revolutionized the treatment and diagnosis of haematological and solid organ malignancies; bringing benefit to millions of patients over the past decades. Recent achievements include conjugating antibodies with toxic payloads resulting in superior efficacy and/or reduced toxicity, development of molecular imaging techniques targeting specific antigens for use as predictive and prognostic biomarkers, the development of novel bi- and tri-specific antibodies to enhance therapeutic benefit and abrogate resistance and the success of immunotherapy agents. In this chapter, we review an overview of antibody structure and function relevant to cancer therapy and provide an overview of pivotal clinical trials which have led to regulatory approval of monoclonal antibodies in cancer treatment. We further discuss resistance mechanisms and the unique side effects of each class of antibody and provide an overview of emerging therapeutic agents.


Assuntos
Anticorpos Monoclonais/farmacologia , Imunoterapia , Neoplasias/terapia , Ensaios Clínicos como Assunto , Humanos
2.
Recent Results Cancer Res ; 214: 71-91, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473849

RESUMO

Bispecific T cell engagers are antibody constructs directed to a tumor-specific target on the one hand and to CD3-positive T cells on the other hand. Blinatumomab is a compound with specificity for the pan-B cell marker CD19. Clinical activity was tested in relapsed and refractory (R/R) non-Hodgkin's Lymphoma (NHL), R/R acute lymphoblastic leukemia (ALL), and ALL patients with minimal residual disease. Trials have already been started in de novo ALL. The most clinically relevant toxicities are neurologic events and cytokine release syndrome as with other T cell-activating therapies. The mechanisms of resistance are not fully understood. Higher leukemia load and later stage disease represent unfavorable factors. Besides, an upregulation of regulatory T cells and inhibitory molecules like PD-1/PD-L1 may have a role as the loss of target by several mechanisms. The future will show whether the use of bispecifics in ALL can change the standard treatment algorithms and whether bispecific T cell engagers will also be successfully used in other malignant entities.


Assuntos
Anticorpos Biespecíficos/farmacologia , Linfoma não Hodgkin/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T/citologia , Antígenos CD19 , Ensaios Clínicos como Assunto , Humanos , Neoplasia Residual/terapia
3.
Recent Results Cancer Res ; 214: 93-128, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31473850

RESUMO

As a specifically programmable, living immunotherapeutic drug, chimeric antigen receptor (CAR)-modified T cells are providing an alternative treatment option for a broad variety of diseases including so far refractory cancer. By recognizing a tumor-associated antigen, the CAR triggers an anti-tumor response of engineered patient's T cells achieving lasting remissions in the treatment of leukemia and lymphoma. During the last years, significant progress was made in optimizing the CAR design, in manufacturing CAR-engineered T cells, and in the clinical management of patients showing promise to establish adoptive CAR T cell therapy as an effective treatment option in the forefront.


Assuntos
Imunoterapia Adotiva , Neoplasias/terapia , Receptores de Antígenos Quiméricos , Antígenos de Neoplasias/imunologia , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T , Linfócitos T/imunologia
4.
Medicine (Baltimore) ; 98(40): e17276, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577719

RESUMO

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer in adults, and patients with advanced ccRCC have a 5-year survival rate of <30%. The poor prognosis of ccRCC is closely related to its lacking of potential therapeutic and prognostic biomarkers. This meta-analysis aimed to elucidate the precise prognostic value of long non-coding RNAs (lncRNAs) in patients with ccRCC. METHODS: A literature search was performed in related databases up to January 31, 2019. Hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) were calculated to explore the relationship between special lncRNAs expression and survival in patients with ccRCC. RESULTS: After literature researching, a total of 16 studies, including 13 lncRNAs were identified. The data from studies that investigated the association between lncRNA expression and survival outcomes in patients with ccRCC were extracted. Results revealed that lncRNAs expression was significantly associated with poor overall survival (OS) outcome in patients with ccRCC (HR = 1.71, 95%CI = 1.40-2.01 in up-regulated subgroup; HR = 0.53, 95% CI = 0.25-0.80 in down-regulated subgroup). The overexpression of PVT1 was significantly associated with poor OS in ccRCC (HR = 1.51, 95% CI = 1.02-2.00). Meanwhile, up-regulation of LUCAT1 was significantly related to worse OS in ccRCC patients (HR = 1.51, 95% CI = 1.01-2.00). CONCLUSIONS: These results suggest that lncRNAs could be used to predict unfavorable prognosis and function as potential prognostic biomarkers in ccRCC.


Assuntos
Carcinoma de Células Renais/genética , Carcinoma de Células Renais/mortalidade , Neoplasias Renais/genética , Neoplasias Renais/mortalidade , RNA Longo não Codificante/genética , Fatores Etários , Biomarcadores Tumorais , Carcinoma de Células Renais/patologia , Proliferação de Células , Ensaios Clínicos como Assunto , Regulação para Baixo , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/patologia , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Fatores Sexuais , Taxa de Sobrevida , Carga Tumoral , Regulação para Cima
5.
Rev Med Suisse ; 15(668): 1920-1924, 2019 Oct 23.
Artigo em Francês | MEDLINE | ID: mdl-31643152

RESUMO

Both cesarean surgery and induction of labor have become common procedures performed in all labor wards in an attempt to reduce adverse obstetrical and neonatal outcomes. Thus, recent evidence, led by the ARRIVE Trial, demonstrated that elective induction at 39 weeks reduced the rates of cesarean deliveries and of hypertensive disorders of pregnancy. However, some concerns must be addressed, as the benefits of universal policies have to be outweighed with the current circumstances of implementation, the economic impact, the number of procedures needed to effectively reduce complications, and, above all, women's perception towards this approach. Therefore, it would be interesting to explore individualization strategies, instead of general recommendations, to offer personalized care.


Assuntos
Cesárea , Ensaios Clínicos como Assunto , Trabalho de Parto Induzido , Obstetrícia/métodos , Obstetrícia/normas , Cesárea/psicologia , Cesárea/normas , Procedimentos Cirúrgicos Eletivos/psicologia , Procedimentos Cirúrgicos Eletivos/normas , Feminino , Humanos , Trabalho de Parto Induzido/psicologia , Trabalho de Parto Induzido/normas , Gravidez , Resultado da Gravidez
6.
J Assoc Physicians India ; 67(10): 75-76, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31571459

RESUMO

A good quality research requires the incorporation of good ethical practices throughout the conduct of the study. An efficient Ethics Committee will facilitate such a research at the site, and can achieve the major objective of ICH-GCP (International Conference on Harmonisation -Good Clinical Practice) guidelines. Awareness of the changing rules among the stakeholders of clinical studies will ensure good clinical practice by safeguarding and protecting the rights, safety and well-being of the research participants. The draft of the New Drugs and Clinical Trials Rules was published in the Gazette of India by central government on March 19, 2019. Keeping abreast of the latest rules are essential for the uninterrupted conduct of clinical studies. We sought to give a summary of important changes in the new rules and to assess those rules from ethical perspective.


Assuntos
Ensaios Clínicos como Assunto , Comissão de Ética , Preparações Farmacêuticas , Índia
7.
BMJ ; 367: l5766, 2019 10 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645328

RESUMO

OBJECTIVE: To determine the extent to which late stage development of new drugs relies on support from public funding. DESIGN: Cohort study. SETTING: All new drugs containing one or more new molecular entities approved by the US Food and Drug Administration (FDA) between January 2008 and December 2017 via the new drug application pathway. MAIN OUTCOME MEASURES: Patents or drug development histories documenting late stage research contributions by a public sector research institution or a spin-off company, as well as each drug's regulatory approval pathway and first-in-class designation. RESULTS: Over the 10 year study period, the FDA approved 248 drugs containing one or more new molecular entities. Of these drugs, 48 (19%) had origins in publicly supported research and development and 14 (6%) originated in companies spun off from a publicly supported research program. Drugs in these groups were more likely to receive expedited FDA approval (68% v 47%, P=0.005) or be designated first in class (45% v 26%, P=0.007), indicating therapeutic importance. CONCLUSIONS: A review of the patents associated with new drugs approved over the past decade indicates that publicly supported research had a major role in the late stage development of at least one in four new drugs, either through direct funding of late stage research or through spin-off companies created from public sector research institutions. These findings could have implications for policy makers in determining fair prices and revenue flows for these products.


Assuntos
Ensaios Clínicos como Assunto/economia , Aprovação de Drogas/economia , Setor Público/economia , Pesquisa Médica Translacional/economia , Ensaios Clínicos como Assunto/estatística & dados numéricos , Estudos de Coortes , Aprovação de Drogas/legislação & jurisprudência , Aprovação de Drogas/estatística & dados numéricos , Humanos , Patentes como Assunto/estatística & dados numéricos , Setor Público/estatística & dados numéricos , Pesquisa Médica Translacional/estatística & dados numéricos , Estados Unidos , United States Food and Drug Administration/legislação & jurisprudência , United States Food and Drug Administration/estatística & dados numéricos
9.
Rinsho Ketsueki ; 60(9): 1193-1198, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597843

RESUMO

In 2018 the practical guidelines for hematological malignancies, edited by Japanese Society of Hematology, underwent major revision for the first time in five years. R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) remains the standard treatment for diffuse large B-cell lymphoma (DLBCL) in line with the prior 2013 guidelines. R-CHOP has been considered as the standard treatment for DLBCL since early 2000s, when a 20% improvement in survival was observed when adding rituximab to CHOP. Following this, several clinical trials were conducted, but most attempts to exceed R-CHOP have failed. Moreover, this evidence has raised further research questions. In this report, the current evidence and the problems associated with DLBCL treatments have been reviewed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Anticorpos Monoclonais Murinos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Ensaios Clínicos como Assunto , Ciclofosfamida/uso terapêutico , Doxorrubicina/uso terapêutico , Humanos , Prednisona/uso terapêutico , Rituximab , Resultado do Tratamento , Vincristina/uso terapêutico
10.
Rev Prat ; 69(6): 607-611, 2019 Jun.
Artigo em Francês | MEDLINE | ID: mdl-31626415

RESUMO

The first administrations of a molecule to humans, so-called phase I studies of drug development, follow experimental animal studies which allow to have a first assessment of the pharmacological effects and toxicity of the molecule under development. Typically, these studies are performed in "healthy" subjects or in relapsing patients with cancer. Participants' safety is a priority. Trained professionals administer single doses, followed by repeated doses, in authorized medical centres. They allow to study the pharmacokinetic and pharmacodynamic profile of tested molecules in humans and to explore some sources of variability of these parameters. These studies are highly regulated and their methodology is fairly standardized.


Assuntos
Ensaios Clínicos como Assunto , Desenvolvimento de Medicamentos , Indústria Farmacêutica , Relação Dose-Resposta a Droga , Desenvolvimento de Medicamentos/legislação & jurisprudência , Indústria Farmacêutica/legislação & jurisprudência , Guias como Assunto , Humanos
11.
Anticancer Res ; 39(10): 5285-5296, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31570423

RESUMO

Triple-negative breast cancer (TNBC) is characterized by a lack of expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) and unfortunately is not associated with good prognosis. Treatment of breast cancer mainly depends on chemotherapy, due to the lack of specifically approved targeted therapies for TNBC. It is of paramount importance to find new therapeutic approaches, as resistance to chemotherapy frequently occurs. Herein, we present clinical studies published within the last five years, in order to reveal possible targeted therapies against TNBC. We aimed to discuss factors against TNBC, such as tyrosine kinase inhibitors, anti-androgens, poly ADP-ribose polymerase-1 (PARP-1) inhibitors, anti-angiogenic factors, immune checkpoints and histone deacetylase inhibitors (HDACI). Furthermore, the PI3K/AKT/mTOR pathway seems to be a promising field for the development of new anti-TNBC targeted therapies. Data from 18 clinical trials with patients suffering from TNBC were summarized and presented descriptively.


Assuntos
Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Ensaios Clínicos como Assunto , Feminino , Humanos , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/metabolismo , Transdução de Sinais/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto Jovem
12.
Lancet ; 394(10200): 793-804, 2019 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-31478503

RESUMO

Antibody-drug conjugates (ADCs) are immunoconjugates comprised of a monoclonal antibody tethered to a cytotoxic drug (known as the payload) via a chemical linker. The ADC is designed to selectively deliver the ultratoxic payload directly to the target cancer cells. To date, five ADCs have received market approval and over 100 are being investigated in various stages of clinical development. In this Therapeutics paper, we review recent clinical experience with the approved ADCs and other promising late-stage candidates on the horizon, following an overview of the biology and chemistry of ADCs and how the individual components of an ADC (antibody [or target], linker and conjugation chemistry, and cytotoxic payload) influence its activity. We briefly discuss opportunities for enhancing ADC efficacy, drug resistance, and future perspectives for this novel antibody-based molecular platform, which has great potential to make a paradigm shift in cancer chemotherapy.


Assuntos
Anticorpos Monoclonais , Antineoplásicos Imunológicos , Imunoconjugados , Neoplasias/tratamento farmacológico , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/farmacologia , Antineoplásicos Imunológicos/administração & dosagem , Antineoplásicos Imunológicos/efeitos adversos , Antineoplásicos Imunológicos/farmacocinética , Antineoplásicos Imunológicos/farmacologia , Ensaios Clínicos como Assunto , Humanos , Imunoconjugados/administração & dosagem , Imunoconjugados/efeitos adversos , Imunoconjugados/farmacocinética , Imunoconjugados/farmacologia
13.
Cancer Treat Rev ; 79: 101887, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491661

RESUMO

Small cell lung cancer (SCLC) was defined as a "recalcitrant cancer" because of its dismal prognosis and lack of outcome improvements in the last 30 years. Immunotherapy with checkpoint inhibitors revolutionized treatment in many cancer types and results from the IMpower133 study, a double-blind placebo-controlled phase III trial, showed overall survival benefit for atezolizumab when added to standard platinum-etoposide chemotherapy in first-line SCLC setting for the first time since years. Trials with other checkpoint inhibitors, e.g. pembrolizumab, durvalumab, nivolumab and ipilimumab, are ongoing in various settings, but, to date, there are no defined factors to identify patients who are more likely to benefit from such treatments. This review summarizes results of immunotherapy trials in SCLC for first-line, maintenance and further-line therapies for single-agents and combinations with checkpoint inhibitors. Predictive factors from these trials are reviewed in order to identify their clinical value, with particular emphasis on PD-L1 expression on both tumor cells and in stroma, especially in pembrolizumab-treated patients, and tumor mutational burden, for patients treated with the ipilimumab and nivolumab combination.


Assuntos
Imunoterapia , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/terapia , Carcinoma de Pequenas Células do Pulmão/imunologia , Carcinoma de Pequenas Células do Pulmão/terapia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Terapia Combinada , Humanos , Imunomodulação/efeitos dos fármacos , Imunoterapia/métodos , Imunoterapia/tendências , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Terapia de Alvo Molecular , Carcinoma de Pequenas Células do Pulmão/mortalidade , Carcinoma de Pequenas Células do Pulmão/patologia , Resultado do Tratamento
14.
Cancer Treat Rev ; 79: 101888, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31491663

RESUMO

Metaplastic breast carcinomas (MPBC) are rare, aggressive and relatively chemorefractory tumors with a high unmet need. While most are "triple negative" and lack expression of estrogen, progesterone and HER2 receptors, MPBC are associated with worse outcomes compared to conventional triple negative invasive tumors. MPBCs are genetically heterogeneous and harbor somatic mutations, most frequently in TP53, PIK3CA and PTEN, with emerging studies suggesting a role for novel targeted therapies. These tumors have also been associated with overexpression of PD-L1 and tumor-infiltrating lymphocytes suggesting an endogenous immune response and therefore a rationale for treatment with immunotherapies. Here, we focus on therapeutic options for this difficult to treat breast cancer subtype and encourage physicians to consider targeted therapies/immunotherapies as part of ongoing clinical trials.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Animais , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Gerenciamento Clínico , Transição Epitelial-Mesenquimal , Feminino , Variação Genética , Humanos , Estadiamento de Neoplasias , Células-Tronco Neoplásicas/metabolismo , Resultado do Tratamento
16.
Soins ; 64(838): 13-19, 2019 Sep.
Artigo em Francês | MEDLINE | ID: mdl-31542112

RESUMO

The number of hospital-based clinical trials is resulting in the growing involvement of nurses. A cross-sectional study in five hospitals involving 60 nurses assessed the clinical research activities, the time allocated and the training level. The results suggest that identifying specific nursing time devoted to clinical research may influence the activities carried out. Improving the definition of these activities could facilitate their integration into nursing practice.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Recursos Humanos de Enfermagem no Hospital/psicologia , Estudos Transversais , Hospitais , Humanos
18.
Codas ; 31(4): e20180176, 2019 Sep 02.
Artigo em Português, Inglês | MEDLINE | ID: mdl-31483040

RESUMO

PURPOSE: To analyze the effects of electrical stimulation on the salivary flow of head and neck cancer patients with radiotherapy-induced hyposalivation. RESEARCH STRATEGIES: Searches were made in the Medline (via Pubmed), Cochrane Library, Scopus and Lilacs databases. SELECTION CRITERIA: Selection included clinical trials that evaluated salivary flow objectively, published in the last 10 years in either Portuguese, English or Spanish. DATA ANALYSIS: The PEDro scale was used for the methodological evaluation of the studies. RESULTS: The search strategy resulted in 21 publications, 17 of which were excluded, hence there were 4 articles left. The included studies had a total of 212 participants, all of whom had an increase in salivary flow, both through the electroacupuncture method and direct application on the salivary glands. The score obtained through the PEDRo scale was low, evidencing questionable methodological quality and risk of bias. CONCLUSION: The included studies demonstrate the clinical potential of TENS to increase the salivary flow of head and neck cancer patients treated with RT.


Assuntos
Estimulação Elétrica , Radioterapia/efeitos adversos , Xerostomia/terapia , Ensaios Clínicos como Assunto , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Xerostomia/etiologia
19.
Int J Nanomedicine ; 14: 4449-4460, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417253

RESUMO

Curcumin as a hydrophobic polyphenol is extracted from the rhizome of Curcuma longa. Curcumin is widely used as a dietary spice and a topical medication for the treatment of inflammatory disorders in Asia. This compound also possesses remarkable anti-inflammatory and neuroprotective effects with the ability to pass from the blood brain barrier. Based on several pharmacological activities of curcumin, it has been introduced as an ideal candidate for different neurological disorders. Despite the pleiotropic activities of curcumin, poor solubility, rapid clearance and low stability have limited its clinical application. In recent years, nano-based drug delivery system has effectively improved the aqueous solubility and bioavailability of curcumin. In this review article, the effects of curcumin nanoparticles and their possible mechanism/s of action has been elucidated in various central nervous system (CNS)-related diseases including Parkinson's disease, Huntington disease, Alzheimer's disease, Multiple sclerosis, epilepsy and Amyotrophic Lateral Sclerosis. Furthermore, recent evidences about administration of nano-curcumin in the clinical trial phase have been described in the present review article.


Assuntos
Doenças do Sistema Nervoso Central/tratamento farmacológico , Curcumina/uso terapêutico , Nanopartículas/química , Ensaios Clínicos como Assunto , Curcumina/administração & dosagem , Curcumina/farmacologia , Sistemas de Liberação de Medicamentos , Humanos , Fármacos Neuroprotetores/uso terapêutico
20.
Rev Med Suisse ; 15(659): 1426-1430, 2019 Aug 21.
Artigo em Francês | MEDLINE | ID: mdl-31436057

RESUMO

Type 1 diabetes (T1D) management is still complex. Some drugs have been proposed as adjunctive treatment to insulin for type 1 diabetes but results are not encouraging. Sodium-glucose cotransporter 2 (SGLT2) inhibitors act independently of insulin and initial proof-of-concept studies related to their use in T1D led to larger phase 3 trials. Several trials have demonstrated some beneficial and consistent effects as HbA1c, body weight and insulin dose reductions, and lesser glycaemic excursions. Nevertheless, adverse events were also reported, especially a higher rate of diabetic ketoacidosis when using gliflozins in T1D. Balance between positive and negative effects must be carefully studied in the near future with data from real-life and large trials dedicated to this potential new help in T1D.


Assuntos
Diabetes Mellitus Tipo 1 , Inibidores do Transportador 2 de Sódio-Glicose , Glicemia/efeitos dos fármacos , Ensaios Clínicos como Assunto , Diabetes Mellitus Tipo 1/tratamento farmacológico , Cetoacidose Diabética/induzido quimicamente , Humanos , Hipoglicemiantes/uso terapêutico , Insulina/administração & dosagem , Inibidores do Transportador 2 de Sódio-Glicose/efeitos adversos , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico
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