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1.
Rinsho Ketsueki ; 60(9): 1157-1165, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597839

RESUMO

The 8p11 myeloproliferative syndrome (EMS) is a relatively rare hematological malignancy defined by the presence of chromosomal abnormalities associated with fibroblast growth factor-1 gene, located in the 8p11-12.1 chromosomal locus. To date, only around a hundred cases have been reported in the literature. Patients with EMS present with various forms of myeloid/lymphoid malignancies, such as myeloproliferative neoplasms, acute myeloid leukemia, and T- or B-linage lymphoblastic lymphoma, which are frequently associated with eosinophilia. Prognosis of EMS is poor and a standard treatment strategy has not yet been established. In contrast to myeloid/lymphoid neoplasms associated with PDGFR-A or PDGFR-B rearrangement, the tyrosine kinase inhibitor (TKI) imatinib is not an effective therapeutic option for EMS patients. Other types of TKI, i.e., PKC412, sorafenib, ponatinib, dasatinib, and dovitinib, show growth-inhibitory effects against the cells harboring several types of FGFR-1 fusion genes in in vitro studies; however, the usefulness of either drug has not been confirmed by clinical trials. Therefore, at present, allo-hematopoietic stem cell transplantation is the only curative methods for EMS. Very recently, a phase-2 study with pemigatinib, an inhibitor for FGFR1, showed clinical benefits for EMS patients, including major cytogenetic response, suggesting a new therapeutic option for EMS.


Assuntos
Aberrações Cromossômicas , Cromossomos Humanos Par 8/genética , Neoplasias Hematológicas/genética , Transtornos Mieloproliferativos/genética , Ensaios Clínicos Fase II como Assunto , Transplante de Células-Tronco Hematopoéticas , Humanos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos/antagonistas & inibidores
2.
Drugs Today (Barc) ; 55(9): 545-562, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31584572

RESUMO

On November 21, 2018, the U.S. Food and Drug Administration (FDA) approved glasdegib in combination with low-dose cytarabine (LDAC), for the treatment of newly diagnosed acute myeloid leukemia (AML) in patients > 75 years old or who have comorbidities that would be prohibitive of intensive induction chemotherapy. Glasdegib is a small-molecule inhibitor of a component of the hedgehog (HH) pathway, an upregulated pathway in leukemia and leukemia stem cells that is associated with relapse, drug resistance and poor survival. Preclinical studies suggested that glasdegib could sensitize AML cells to chemotherapy. FDA approval was based on a randomized, placebo-controlled, phase II trial in elderly or infirmed adults with new AML, unable to receive intensive induction chemotherapy, in whom the addition of glasdegib to LDAC nearly doubled the median overall survival compared with LDAC alone. In this report, we examine the preclinical development of glasdegib, its pharmacology and the clinical investigation that demonstrated its safety and efficacy, resulting in its approval. Additionally, we highlight ongoing investigation and future applications of this therapy.


Assuntos
Benzimidazóis/uso terapêutico , Leucemia Mieloide Aguda/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Compostos de Fenilureia/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Ensaios Clínicos Fase II como Assunto , Citarabina , Aprovação de Drogas , Humanos , Quimioterapia de Indução , Ensaios Clínicos Controlados Aleatórios como Assunto , Estados Unidos , United States Food and Drug Administration
3.
Cancer Radiother ; 23(6-7): 496-499, 2019 Oct.
Artigo em Francês | MEDLINE | ID: mdl-31471251

RESUMO

Stereotactic radiotherapy of oligometastases, mono- or hypofractionated, represents a fundamental change in the practice of the specialty as it was developed for a century. Despite the great heterogeneity of sites, techniques, and doses, most studies found a high local control rate, around 70 to 90% at 2 years, and reduced toxicity, around 5% of grade 3 at 2 years. Four main phase II and III trials are underway in France. Future research concerns the association of stereotactic radiotherapy with immunotherapy or different conventional chemotherapy protocols, the identification of the best clinical presentations, and optimization of fractionation and biological dose for poor prognosis localizations.


Assuntos
Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Neoplasias/radioterapia , Radiocirurgia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Ósseas/radioterapia , Neoplasias Ósseas/secundário , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/radioterapia , Terapia Combinada/métodos , Previsões , França , Humanos , Imunoterapia , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/radioterapia , Masculino , Metástase Neoplásica , Neoplasias/patologia , Neoplasias/terapia , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/radioterapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia
4.
Undersea Hyperb Med ; 46(4): 385-397, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509895

RESUMO

Over the past four decades, hyperbaric oxygen (HBO2) therapy has played a prominent role in both the prevention and treatment of mandibular osteoradionecrosis (ORN). It has done so on the strength of laboratory observations and clinical reports, yet only limited efficacy data. This dual role has come under increasing scrutiny in the modern radiotherapy (RT) and surgical eras. The ability to spare healthy "non-target" tissue has markedly improved since the two-dimensional planning and delivery techniques in use when HBO2's prophylactic value was first demonstrated. A recent study failed to identify this same benefit in patients who received high-precision imaging and conformal RT. HBO2 therapy is under challenge as preferred treatment for early stage ORN. A recently introduced "fibroatrophic" mechanism contrasts with the hypovascular-hypocellular-hypoxic injury pattern that formed the basis for HBO2's therapeutic use. This alternative pathophysiologic state appears to benefit from an oral antioxidant medication regimen. The continuing necessity of HBO2 in support of mandibular reconstruction for advanced ORN is in question. Microsurgery-based vascularized bone flaps increasingly represent standard care, invariably in the absence of perioperative HBO2. Renewed interest in hyperbaric oxygen as a radiation sensitizer offers some promise. Hypoxia remains a critical radio-resistant factor in many solid tumors. Malignant gliomas have been a primary focus of several small studies, with resulting improvements in local control and median survival. Hyperbaric radiation sensitization has recently addressed oropharyngeal cancer. Preliminary data indicates that addition of HBO2 to chemo-radiation standard of care is technically feasible, well tolerated and safe. A Phase II efficacy trial will investigate the potential for of HBO2 to improve progression-free and relapse-free survival in newly diagnosed locally advanced head and neck cancers. What follows is a review and summary of relevant peer-reviewed literature.


Assuntos
Neoplasias de Cabeça e Pescoço/radioterapia , Oxigenação Hiperbárica , Mandíbula/efeitos da radiação , Osteorradionecrose/terapia , Tolerância a Radiação , Hipóxia Celular/efeitos da radiação , Ensaios Clínicos Fase II como Assunto , Ácido Clodrônico/uso terapêutico , Combinação de Medicamentos , Humanos , Mandíbula/cirurgia , Osteorradionecrose/patologia , Osteorradionecrose/prevenção & controle , Pentoxifilina/uso terapêutico , Radioterapia Conformacional/efeitos adversos , Procedimentos Cirúrgicos Reconstrutivos , Tocoferóis/uso terapêutico , Extração Dentária
5.
Expert Opin Investig Drugs ; 28(8): 733-740, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31347405

RESUMO

Introduction: Cachexia is frequent in chronic diseases and especially during cancer development. Multiple definitions of cachexia have been proposed; it may be considered a multifactorial complex syndrome that presents with progressive unintentional weight loss and wasting of muscle mass and adipose tissue. Area covered: This article covers phase-I and phase-II clinical trials of investigational drugs for cancer cachexia. We performed a search on PubMed with keywords as cancer cachexia, phase-I/phase-II trial, drug, identifying articles relevant to this review. Studies were conducted using compounds, including anabolic agents such as ghrelin analogs, selective androgen receptor modulators, as well as anti-inflammatory drugs such as thalidomide, OHR, anti-interleukin antibody, cannabinoids, and omega-3 supplements. We also describe the mechanisms of action of these molecules and their phase-I and phase-II study design. The major outcomes were appetite stimulation, weight gain, improvement of muscle mass and function, modulation of inflammation, and quality of life. Expert opinion: The molecules discussed act on molecular pathways involved in cancer cachexia; they modulate appetite, anabolic effects, inflammation and direct interaction with muscle. Considering the multifactorial aspects of the cachexia syndrome, the combination of these drugs with metabolic and nutritional interventions may represent the most promising therapeutic approach to cancer cachexia.


Assuntos
Caquexia/tratamento farmacológico , Drogas em Investigação/uso terapêutico , Neoplasias/complicações , Apetite/efeitos dos fármacos , Caquexia/etiologia , Caquexia/fisiopatologia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/farmacologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/patologia , Apoio Nutricional/métodos , Qualidade de Vida , Projetos de Pesquisa
6.
J Cancer Res Clin Oncol ; 145(10): 2547-2554, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31324979

RESUMO

PURPOSE: External beam radiotherapy (EBRT) is an effective treatment option for low- and favorable intermediate-risk prostate cancer (PCa) and it is usually delivered in conventional fractionation or with moderate hypofractionation (hRT), with comparable results. In the last years, a new treatment approach with stereotactic body radiotherapy (SBRT) has shown promising results. The aim of the present study was to directly compare the toxicity and outcome between hRT and SBRT in low and favorable intermediate PCa patients. MATERIALS AND METHODS: The hRT schedules were: 71.4 Gy or 74.2 Gy in 28 fractions for low- or favorable intermediate-risk PCa, respectively, while the SBRT schedules were: 35 Gy or 37.5 Gy in five fractions, for low or favorable intermediate risk, respectively. Toxicity assessment was performed according to CTCAE v5.0 grading. The International Prostatic Symptoms Score (IPSS) was also recorded. RESULTS: One hundred forty-nine patients were analyzed, overall 81 (54.36%) patients were low risk and 68 (45.64%) were favorable intermediate risk. Sixty-nine (46.3%) patients were treated with hypo-RT and 80 (53.7%) with SBRT. Median follow-up was 33 months (range 11-58 months). The actuarial survival rate was 98.66%. The 3-years BFS rates were 95.5% and 100% for hRT and SBRT, respectively (p = 0.051). One case (0.6%) of acute grade 3 urinary toxicity occurred in a patient with favorable intermediate risk treated with hRT. He initially suffered gross hematuria and acute urinary retention not treatable with urinary catheter, therefore a suprapubic catheter was placed and steroids were administered. No differences in acute, late or severe toxicity were detected. CONCLUSION: Stereotactic body radiotherapy reported a good clinical outcome and safe toxicity profile. Results are comparable to hRT, but a longer follow-up is needed to assess the late effectiveness and toxicity.


Assuntos
Neoplasias da Próstata/radioterapia , Hipofracionamento da Dose de Radiação , Radiocirurgia , Idoso , Idoso de 80 Anos ou mais , Ensaios Clínicos Fase II como Assunto , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Antígeno Prostático Específico , Neoplasias da Próstata/diagnóstico , Neoplasias da Próstata/mortalidade , Radiocirurgia/efeitos adversos , Radiocirurgia/métodos , Planejamento da Radioterapia Assistida por Computador , Estudos Retrospectivos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
7.
Medicine (Baltimore) ; 98(28): e16372, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31305435

RESUMO

BACKGROUND: Acute graft-vs-host disease (aGVHD) is a common complication of allogenic hematopoietic stem-cell transplantation (allo-HSCT) and skin is the most common and often the 1st site at which aGVHD develops. Cutaneous aGVHD is usually treated with oral and/or topical corticosteroids as the 1st-line treatment; however, steroid-refractory aGVHD not only impairs patients' quality of life but also causes significant morbidity and mortality after allo-HSCT. Narrow-band ultraviolet B (NB-UVB) phototherapy has been utilized for a wide range of immunologic inflammatory skin diseases, but there is limited information on the efficacy, safety, and biomarkers for response prediction of NB-UVB for cutaneous aGVHD. AIMS: The purpose of this study is to investigate the efficacy and safety of NB-UVB phototherapy for steroid-refractory cutaneous aGVHD. PATIENTS AND METHODS: A total of 40 subjects aged from 16 to 70 years with steroid-refractory cutaneous aGVHD after allo-HSCT will be included in the trial. Patients with worse than stage 2 intestine/liver aGVHD will be excluded. Eligible patients will undergo NB-UVB phototherapy until resolution or further worsening of rash or occurrence of an unmanageable adverse event. The primary endpoint is the overall response rate. The secondary outcomes include rates for complete response, partial response, stable disease, progressive disease, duration of response, sparing effect on calcineurin inhibitors and/or corticosteroids, safety, and predictive biomarkers for treatment response. ETHICS AND DISSEMINATION: The protocol has been approved by the institutional Clinical Research Review Board of Kyoto Prefectural University of Medicine. Written informed consent will be obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. TRIAL REGISTRATION: Trial registration numbers UMIN000032426 and jRCTs052180005.


Assuntos
Ensaios Clínicos Fase II como Assunto , Doença Enxerto-Hospedeiro/terapia , Dermatopatias/terapia , Transplante de Células-Tronco , Terapia Ultravioleta , Doença Aguda , Adolescente , Adulto , Idoso , Anti-Inflamatórios/uso terapêutico , Resistência a Medicamentos , Humanos , Pessoa de Meia-Idade , Retratamento , Dermatopatias/etiologia , Esteroides/uso terapêutico , Transplante Homólogo , Terapia Ultravioleta/efeitos adversos , Terapia Ultravioleta/métodos , Adulto Jovem
8.
Medicine (Baltimore) ; 98(26): e16176, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31261551

RESUMO

INTRODUCTION: Re-irradiation after radiotherapy is a common treatment for locally recurrent esophageal cancer. However, the side effects of re-irradiation are serious. The most serious adverse reactions of re-irradiation include esophageal perforation and hemorrhage caused by esophageal perforation. Studies have shown that pulsed low-dose rate radiotherapy (PLDR) induces a hypersensitivity effect on tumor tissue and a hyper-repair effect on normal tissue, which can simultaneously reduce damage on the normal tissue and increase the therapeutic effect on the tumor. The objective of this study is to explore whether PLDR can reduce rate of esophageal perforation and improve efficacy in patients with recurrent esophageal squamous cell carcinoma (ESCC) after radiotherapy. METHODS AND ANALYSIS: This study is a prospective, multi-center, open, single-arm clinical trial designed to enroll 27 patients with locally recurrent ESCC after radiotherapy with or without chemotherapy. Re-irradiation will be performed using intensity modulated radiation therapy in 50 Gy/25 fractions. The strategy of PLDR includes dividing 2 Gy into 10 fractions, and administering each irradiating dose of 20 cGy at an interval of 3 minutes before the next low-dose irradiation. The actual dose rate of administration each time will be 16.67 cGy /minute. The primary endpoint in this study is the rate of esophageal perforation. The secondary endpoints are the objective remission rate, the palliative effect on quality of life and pain, and the time of disease progression. The observation time is 2 years after the end of the study. TRIAL REGISTRATION: Clinical trial number: ChiCTR1900020609.


Assuntos
Ensaios Clínicos Fase II como Assunto , Neoplasias Esofágicas/radioterapia , Carcinoma de Células Escamosas do Esôfago/radioterapia , Estudos Multicêntricos como Assunto , Recidiva Local de Neoplasia/radioterapia , Reirradiação , Quimiorradioterapia , Neoplasias Esofágicas/tratamento farmacológico , Carcinoma de Células Escamosas do Esôfago/tratamento farmacológico , Humanos , Recidiva Local de Neoplasia/tratamento farmacológico , Seleção de Pacientes , Dosagem Radioterapêutica , Radioterapia de Intensidade Modulada/métodos
9.
Parasit Vectors ; 12(1): 298, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31196145

RESUMO

BACKGROUND: Urinary schistosomiasis, caused by Schistosoma haematobium, remains a significant public health problem worldwide, despite years of efforts to control it. Haematuria is one of the notable indirect indicators of S. haematobium infection and is commonly assessed along with other routine screens using a urinary dipstick test. A portable "field friendly" electronic analyser would offer an automated and thus more objective read-out compared to visual-read dipstick methods. METHODS: Within the framework of a Phase 2 praziquantel dose finding study in preschool- and school-aged children infected with S. haematobium, in southern Côte d'Ivoire, we compared a visual-read of the urine dipstick strips (Multistix PRO, Siemens Healthcare Diagnostics) to an automated reader (CLINITEK Status+ analyser™ Siemens Healthcare Diagnostics). Urine samples were collected from 148 pre-school aged and 152 school-aged children for urinalysis. Values were compared using a linear weighted kappa statistic and Bland-Altman analysis. RESULTS: A very good correlation between the two methods for nitrites and haematuria was observed (κ coefficient of 0.88 and 0.82, respectively), while a good correlation was observed for leukocytes (κ coefficient of 0.63) A moderate to fair correlation was calculated (κ coefficient ≤ 0.6) for all other parameters. When the results were stratified according to infection intensity, the agreements were stronger from the high infection intensity sample measurements, for most of the parameters. CONCLUSION: Our results demonstrate the device's utility in detecting haematuria and nitrites but underline the need for further development of this tool in order to improve its performance in the field.


Assuntos
Hematúria/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito/normas , Kit de Reagentes para Diagnóstico/normas , Esquistossomose Urinária/diagnóstico , Urinálise/instrumentação , Animais , Criança , Ensaios Clínicos Fase II como Assunto , Costa do Marfim/epidemiologia , Feminino , Humanos , Masculino , Schistosoma haematobium/isolamento & purificação , Esquistossomose Urinária/urina , Urinálise/normas
10.
Gynecol Oncol ; 154(3): 539-546, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31230821

RESUMO

OBJECTIVE: Low-grade epithelial ovarian cancers (EOC), constitute the minority among all epithelial cancers. Our study objective was to focus on low-grade recurrent EOC and compare the survival with high-grade disease, as well as in regard to "platinum-sensitive" and "-resistant" recurrences according to platinum-free interval. METHODS: This is an exploratory analysis within the North-Eastern German Society of Gynecological Oncology (NOGGO) database including five randomized phase II/III trials comparing different chemotherapy regimens in recurrent EOC. We conducted survival analyses and cox-proportional regression models. RESULTS: Out of 1050 patients having the first recurrence, 42 (4%) patients had low-grade and 1008 (96%) patients had high-grade disease. In the subgroup of platinum-sensitive recurrences, progression-free survival (PFS) (8.7 m vs 9.7 m, p = 0.7) and overall survival (OS) (23.9 m vs 24.8 m, p = 0.9) did not differ between low-grade and high-grade diseases. In platinum-resistant recurrences, patients with low-grade ovarian cancer had significantly better PFS (7.6 m vs 3.6 m, p = 0.03) and OS (41.9 m vs 9.5 m p = 0.002) in comparison to those with high-grade cancer. At low-grade EOC, there were no significant PFS (p = 0.91) and OS (p = 0.25) differences between platinum-sensitive and -resistant recurrences. Patients with low-grade non-serous histology had lower PFS with compared to those with low-grade serous histology (p = 0.004). At cox regression analysis presence of ascites and residual disease after secondary cytoreductive surgery were independently associated with poor PFS within low-grade recurrent EOC. CONCLUSION: Our study indicates, platinum-free interval does not have any prognostic significance at recurrent low-grade EOC and non-serous histology is associated with poorer outcome in recurrence. Secondary surgical cytoreduction to no-gross residual disease and ascites are independently associated with disease progression.


Assuntos
Carcinoma Epitelial do Ovário/tratamento farmacológico , Neoplasias Ovarianas/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Epitelial do Ovário/mortalidade , Carcinoma Epitelial do Ovário/patologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Recidiva Local de Neoplasia/tratamento farmacológico , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/patologia , Compostos Organoplatínicos/administração & dosagem , Neoplasias Ovarianas/mortalidade , Neoplasias Ovarianas/patologia , Prognóstico , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Análise de Sobrevida , Topotecan/administração & dosagem , Adulto Jovem
11.
Expert Opin Investig Drugs ; 28(7): 629-642, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31232099

RESUMO

INTRODUCTION: Actinic keratoses (AKs) are limited areas of irregular epidermal growth on a background of excessive solar exposure. The entire sun-damaged skin is considered a field of cancerization with multiple visible and subclinical lesions. AK management requires field-directed therapies to block lesion relapse and prevent squamous cell carcinoma (SCC). AREAS COVERED: In this review, we focused on phase II clinical trials for AKs, involving well-known agents and newer molecules such as proapoptotic drugs (VDA-1102, SR-T100, oleogel-S10, ICVT, eflornithine), immunomodulants (isotretinoin, tretinoin) and chemopreventive agents (nicotinamide, perillyl alcohol, liposomal T4N5). We used the website 'ClinicalTrials.Gov' as main reference. We selected and discussed completed and ongoing trials and analysed chemical structure and mechanism of action of the investigated molecules. EXPERT OPINION: AK therapy should be tailored on the patient's profile considering first of all the age and site of the AKs, which are relevant parameters for local immune response. The new molecules could be combined to obtain a synergic effect blocking the different steps of skin tumorigenesis. Phase II trials highlight a new therapeutic opportunity to block selectively cell proliferation regulators and work both on the field of cancerization and on the AKs currently present.


Assuntos
Desenvolvimento de Medicamentos/métodos , Drogas em Investigação/farmacologia , Ceratose Actínica/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/prevenção & controle , Proliferação de Células/efeitos dos fármacos , Ensaios Clínicos Fase II como Assunto , Drogas em Investigação/administração & dosagem , Humanos , Ceratose Actínica/complicações , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/prevenção & controle
12.
World J Gastroenterol ; 25(15): 1783-1796, 2019 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-31057294

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is a complex disorder that has evolved in recent years as the leading global cause of chronic liver damage. The main obstacle to better disease management pertains to the lack of approved pharmacological interventions for the treatment of nonalcoholic steatohepatitis (NASH) and NASH-fibrosis-the severe histological forms. Over the past decade, tremendous advances have been made in NAFLD research, resulting in the discovery of disease mechanisms and novel therapeutic targets. Hence, a large number of pharmacological agents are currently being tested for safety and efficacy. These drugs are in the initial pharmacological phases (phase 1 and 2), which involve testing tolerability, therapeutic action, and pharmacological issues. It is thus reasonable to assume that the next generation of NASH drugs will not be available for clinical use for foreseeable future. The expected delay can be mitigated by drug repurposing or repositioning, which essentially relies on identifying and developing new uses for existing drugs. Here, we propose a drug candidate selection method based on the integration of molecular pathways of disease pathogenesis into network analysis tools that use OMICs data as well as multiples sources, including text mining from the medical literature.


Assuntos
Reposicionamento de Medicamentos , Metabolismo dos Lipídeos/efeitos dos fármacos , Cirrose Hepática/prevenção & controle , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Progressão da Doença , Humanos , Fígado/efeitos dos fármacos , Fígado/patologia , Cirrose Hepática/patologia , Redes e Vias Metabólicas/efeitos dos fármacos , Terapia de Alvo Molecular/métodos , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Transdução de Sinais/efeitos dos fármacos
13.
Medicine (Baltimore) ; 98(22): e15522, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31145273

RESUMO

BACKGROUND: The N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (MET) inhibitors show a surprising survival benefit in the treatment of numerous tumors especially in MET-high tumor. Besides their impressive efficacy, fatigue reduced by MET inhibitors is still the safety issue during treatment. Thus, an understanding of this risk in the context of expanding MET-inhibitors use is an important cost and patient safety issue. METHODS: We searched PubMed, Embase, and the Cochrane Library databases for relevant studies up to October 2017. Eligibility criteria included phase II/III trials of MET inhibitors that reported adequate safety profiles of fatigue. The principal summary measures were incidence and relative risk (RR) of all-grade (grade 1-4) and high-grade (grade 3-4) fatigue, respectively. Random-effects model was applied to consider within-study and between-study variation. RESULTS: A total of 5028 patients from 17 clinical trials were identified. The results revealed that the incidences of MET inhibitors-associated all-grade and high-grade fatigue were 41.9% and 9.6%, respectively. The RR of high-grade fatigue was (RR = 1.37; 95% confidence interval, 1.14-1.66; P = .0009), whereas the RR of all-grade fatigue was (RR = 1.02; 95% confidence interval, 0.91-1.15; P = .71). CONCLUSION: Our meta-analysis has demonstrated that MET inhibitors-based treatment is associated with an increased risk of high-grade fatigue compared with control.


Assuntos
Fadiga/induzido quimicamente , Fadiga/epidemiologia , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Incidência , Risco
14.
Drugs Today (Barc) ; 55(5): 297-304, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31131840

RESUMO

The current standard of care for treating HIV infection is the use of three antiretroviral drugs: a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) and a third agent from either the integrase strand transfer inhibitor (INSTI), boosted protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI) classes. In an effort to minimize the long-term adverse effects and cost of antiretroviral therapy, the use of regimens with fewer drugs in the combination has been under active investigation. To this end, the combination of dolutegravir (DTG) plus lamivudine (3TC), two antiretroviral drugs with a long track record of efficacy and safety in the treatment of HIV infection, is undergoing clinical evaluation in treatment-naive HIV-infected participants. The promising results of the PADDLE study, with 90% of study participants achieving the primary endpoint of HIV-1 RNA lower than 50 copies/mL, were confirmed by the results of ACTG A5353, a phase II, single-arm, open-label study. Subsequently, GEMINI-1 and -2, two phase III, double-blind, noninferiority studies, compared DTG + 3TC to a three-drug regimen of DTG, tenofovir disoproxil fumarate and emtricitabine in 1,433 antiretroviral treatment-naive adults, and demonstrated noninferior efficacy at 48 weeks with no emergence of NRTI or INSTI mutations and a more favorable safety profile. This dual regimen should be avoided in those patients with existing mutations and chronic hepatitis B virus infection. In addition, data in patients with CD4 counts less than 200/mm3 is limited.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Infecções por HIV/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Lamivudina/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Estudos de Equivalência como Asunto , HIV-1 , Humanos
15.
Br J Radiol ; 92(1102): 20181031, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31112398

RESUMO

Clinical trials are powerful weapons in the battle against nasopharyngeal carcinoma (NPC). Based on clinical trials conducted in the past two decades, concurrent chemoradiotherapy combined with adjuvant chemotherapy or induction chemotherapy has been recommended as the standard treatment for locoregionally advanced NPC in various guidelines. However, there remain shortcomings concerning current treatment modalities that should be refined in future research. In this article, we review the achievements of published clinical trials for locoregionally advanced NPC and propose future directions for subsequent clinical trials. We believe that refinement of current regimens of chemotherapy, de-intensification of treatment for specific groups of patients, developing personalized treatment based on predictors ( e.g. applying plasma Epstein-Barr virus DNA) and investigating novel therapies, such as targeted therapy and immunotherapy, should be applied with the highest priority when designing clinical trials for locoregionally advanced NPC in the next decade.


Assuntos
Ensaios Clínicos como Assunto/métodos , Carcinoma Nasofaríngeo/terapia , Neoplasias Nasofaríngeas/terapia , Quimiorradioterapia/mortalidade , Quimioterapia Adjuvante/mortalidade , Ensaios Clínicos como Assunto/normas , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , DNA Viral/sangue , Previsões , Herpesvirus Humano 4/genética , Humanos , Imunoterapia/métodos , Quimioterapia de Indução , Adesão à Medicação , Terapia de Alvo Molecular/métodos , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/mortalidade , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/virologia , Meta-Análise em Rede , Medicina de Precisão , Ensaios Clínicos Controlados Aleatórios como Assunto , Taxa de Sobrevida , Fatores de Tempo
16.
Future Microbiol ; 14: 563-580, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31091978

RESUMO

Protection by meningococcal group A, C, W and Y (MenACWY) vaccines against four meningococcal disease-causing serogroups is increasingly important because of changing epidemiologic patterns of meningococcal disease, including recent meningococcal serogroup W outbreaks/disease clusters. The MenACWY vaccine conjugated to tetanus toxoid (MenACWY-TT) has been extensively evaluated across the age spectrum (age ≥6 weeks) in randomized Phase II and III and in postmarketing studies. Results support the robust immunogenicity of MenACWY-TT across ages and coadministration with other vaccines. The safety profile is similar regardless of age, primary versus booster vaccination, or concomitant administration; local (swelling, pain, redness) and systemic (fever, fatigue, headache, drowsiness, loss of appetite, irritability) reactogenicity events are most common. These data support use of MenACWY-TT to protect against MenACWY disease.


Assuntos
Infecções Meningocócicas/imunologia , Infecções Meningocócicas/prevenção & controle , Vacinas Meningocócicas/imunologia , Toxoide Tetânico/imunologia , Vacinas Conjugadas/imunologia , Antígenos de Bactérias/imunologia , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Humanos , Imunogenicidade da Vacina , Vacinas Meningocócicas/administração & dosagem , Vacinas Meningocócicas/efeitos adversos , Neisseria meningitidis/patogenicidade , Ensaios Clínicos Controlados Aleatórios como Assunto , Sorogrupo , Vacinação , Vacinas Conjugadas/administração & dosagem , Vacinas Conjugadas/efeitos adversos
17.
Crit Rev Oncol Hematol ; 139: 67-74, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31112883

RESUMO

Whole-body hyperthermia (WBH) might be beneficial for patients with metastasized solid malignancies when combined with systemic therapy. This review identified and summarized the phase I/II studies (n = 13/14) conducted using this combination of therapies. Most of the phase II studies used radiant heating methods in a thermal dose of 41.8 °C (1 h). All studies used classic chemotherapy. Great inter-study heterogeneity was observed regarding treatment regimes, included patients and reported response rates (12-89%). Ovarian cancer, colorectal adenocarcinoma, lung cancer and sarcoma have been studied most. Most reported toxicity (grade 3/4) was myelosuppression. Treatment related mortality was present (4 patients) in three out 14 phase II studies (350 evaluable patients, over 966 cycles of WBH with chemotherapy). Absence of phase III trials makes the additive value of WBH highly speculative. As modern oncology offers many less invasive treatments options, it is unlikely WBH will ever find its way in routine clinical care.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Regulação da Temperatura Corporal , Hipertermia Induzida/métodos , Neoplasias/terapia , Ensaios Clínicos Fase II como Assunto , Terapia Combinada , Humanos , Prognóstico
20.
BMC Cancer ; 19(1): 373, 2019 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-31014274

RESUMO

BACKGROUND: There is a paucity of plasma-based biomarkers that prospectively segregate the outcome of patients with head and neck squamous-cell carcinoma (HNSCC) treated with chemoradiation therapy (CRT). Plasma extracellular vesicles (EVs) might be an alternative source for discovery of new specific markers present in patients with HNSCC, which could help to re-direct patients to appropriate curative therapies without delay. METHODS: In order to identify new markers in plasma compartments, Cholerae toxin B chain (CTB) and Annexin V (AV) were used to isolate EVs from pooled plasma samples from patients with locally advanced HNSCC who responded (CR, n = 6) or presented incomplete response (NR, n = 6) to CRT. The crude plasma and EVs cargo were screened by antibody array. RESULTS: Of the 370 polypeptides detected, 119 proteins were specific to NR patients while 38 were exclusive of the CR subjects. The Gene Set Enrichment Analysis (GSEA) and Search Tool for the Retrieval of Interacting Genes (STRING) database analysis indicated that the content of circulating plasma EVs might have a relevant function for the tumor intercellular communication in the HNSCC patients. CONCLUSION: This study provides a list of potential markers present in plasma compartments that might contribute to the development of tools for prediction and assessment of CRT response and potentially guide therapeutic decisions in this context.


Assuntos
Biomarcadores Tumorais/sangue , Carcinoma de Células Escamosas/patologia , Quimiorradioterapia/métodos , Vesículas Extracelulares/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/terapia , Ensaios Clínicos Fase II como Assunto , Vesículas Extracelulares/patologia , Feminino , Seguimentos , Neoplasias de Cabeça e Pescoço/sangue , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Análise Serial de Proteínas , Mapas de Interação de Proteínas
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