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1.
Lancet Haematol ; 7(3): e226-e237, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31982039

RESUMO

BACKGROUND: Polycythaemia vera is a myeloproliferative neoplasm characterised by excessive proliferation of erythroid, myeloid, and megakaryocytic components in the bone marrow due to mutations in the Janus kinase 2 (JAK2) gene. Ruxolitinib, a JAK 1 and JAK 2 inhibitor, showed superiority over best available therapy in a phase 2 study in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. We aimed to compare the long-term safety and efficacy of ruxolitinib with best available therapy in patients with polycythaemia vera who were resistant to or intolerant of hydroxyurea. METHODS: We report the 5-year results for a randomised, open-label, phase 3 study (RESPONSE) that enrolled patients at 109 sites across North America, South America, Europe, and the Asia-Pacific region. Patients (18 years or older) with polycythaemia vera who were resistant to or intolerant of hydroxyurea were randomly assigned 1:1 to receive either ruxolitinib or best available therapy. Patients randomly assigned to the ruxolitinib group received the drug orally at a starting dose of 10 mg twice a day. Single-agent best available therapy comprised hydroxyurea, interferon or pegylated interferon, pipobroman, anagrelide, approved immunomodulators, or observation without pharmacological treatment. The primary endpoint, composite response (patients who achieved both haematocrit control without phlebotomy and 35% or more reduction from baseline in spleen volume) at 32 weeeks was previously reported. Patients receiving best available therapy could cross over to ruxolitinib after week 32. We assessed the durability of primary composite response, complete haematological remission, overall clinicohaematological response, overall survival, patient-reported outcomes, and safety after 5-years of follow-up. This study is registered with ClinicalTrials.gov, NCT01243944. FINDINGS: We enrolled patients between Oct 27, 2010, and Feb 13, 2013, and the study concluded on Feb 9, 2018. Of 342 individuals screened for eligibility, 222 patients were randomly assigned to receive ruxolitinib (n=110, 50%) or best available therapy (n=112, 50%). The median time since polycythaemia vera diagnosis was 8·2 years (IQR 3·9-12·3) in the ruxolitinib group and 9·3 years (4·9-13·8) in the best available therapy group. 98 (88%) of 112 patients initially randomly assigned to best available therapy crossed over to receive ruxolitinib and no patient remained on best available therapy after 80 weeks of study. Among 25 primary responders in the ruxolitinib group, six had progressed at the time of final analysis. At 5 years, the probability of maintaining primary composite response was 74% (95% CI 51-88). The probability of maintaining complete haematological remission was 55% (95% CI 32-73) and the probability of maintaining overall clinicohaematological responses was 67% (54-77). In the intention-to-treat analysis not accounting for crossover, the probability of survival at 5 years was 91·9% (84·4-95·9) with ruxolitinib therapy and 91·0% (82·8-95·4) with best available therapy. Anaemia was the most common adverse event in patients receiving ruxolitinib (rates per 100 patient-years of exposure were 8·9 for ruxolitinib and 8·8 for the crossover population), though most anaemia events were mild to moderate in severity (grade 1 or 2 anaemia rates per 100 patient-years of exposure were 8·0 for ruxolitinib and 8·2 for the crossover population). Non-haematological adverse events were generally lower with long-term ruxolitinib treatment than with best available therapy. Thromboembolic events were lower in the ruxolitinib group than the best available therapy group. There were two on-treatment deaths in the ruxolitinib group. One of these deaths was due to gastric adenocarcinoma, which was assessed by the investigator as related to ruxolitinib treatment. INTERPRETATION: We showed that ruxolitinib is a safe and effective long-term treatment option for patients with polycythaemia vera who are resistant to or intolerant of hydroxyurea. Taken together, ruxolitinib treatment offers the first widely approved therapeutic alternative for this post-hydroxyurea patient population. FUNDING: Novartis Pharmaceuticals Corporation.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Interferon alfa-2/uso terapêutico , Interferon-alfa/uso terapêutico , Policitemia Vera/tratamento farmacológico , Polietilenoglicóis/uso terapêutico , Pirazóis/uso terapêutico , Quinazolinas/uso terapêutico , Antivirais/uso terapêutico , Quimioterapia Combinada , Fibrinolíticos/uso terapêutico , Seguimentos , Humanos , Hidroxiureia/administração & dosagem , Pipobromano/administração & dosagem , Prognóstico , Proteínas Recombinantes/uso terapêutico , Taxa de Sobrevida , Fatores de Tempo
2.
Cancer Sci ; 111(2): 679-686, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31828849

RESUMO

The incidence of epidermal growth factor receptor uncommon mutation (EGFRum) is relatively low and patients harboring EGFRum are resistant to the first-generation tyrosine kinase inhibitors (TKI). However, the mechanism of primary resistance remains unclear. Medical records of 98 patients who had never been treated by TKI and who accepted icotinib treatment were collected and followed. The circulating tumor DNA (ctDNA) were detected and analyzed using the next-generation sequencing (NGS) platform after progression on icotinib. The potential primary resistance mechanism of icotinib was explored. A total of 21 (21.4%) and 48 (49%) patients developed primary and acquired resistance to icotinib, respectively. The median progression-free survival (PFS) of primary resistance patients was 1.8 months (0.5-2.3, 95% CI = 1.50-2.10). Before treatment, 52.4% (11/21) of patients carried S768I, 23.8% (5/21) L861Q, 14.3% (3/21) G719X and 14.3% (3/21) exon 20-ins mutations. Approximately 23.8% (5/21) of patients harbored the combined pattern mutations and 76.2% (16/21) of patients harbored the single pattern mutations. The combined pattern with EGFR classical mutation (EGFRcm) had worse PFS than the combined with EGFRum and single pattern (P < .05). There were 6 (28.57%) patients with acquired EGFR extracellular domain mutation, 5 (23.81%) with BCL2L11 loss (BIM deletion polymorphism), 3 (14.29%) with MET amplification, 1 (4.76%) with ERBB2 amplification, 1 (4.76%) with MYC amplification, 1 (4.76%) with PTEN mutation, 1 (4.76%) with PIK3CA mutation and 3 (14.29%) with unknown status. EGFR extracellular domain mutation, BCL2L11 loss, PI3K-AKT-mTOR signaling pathway (PTEN and PIK3CA mutations), MET amplification, ERBB2 amplification or MYC amplification might contribute to molecular mechanisms of primary resistance to icotinib in patients with advanced non-small cell lung cancer harboring uncommon mutant epidermal growth factor receptor. Combined targeted therapy or chemotherapy should be considered in this population.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Éteres de Coroa/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Redes Reguladoras de Genes , Neoplasias Pulmonares/tratamento farmacológico , Quinazolinas/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/genética , China , DNA Tumoral Circulante/análise , Progressão da Doença , Receptores ErbB/genética , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Neoplasias Pulmonares/genética , Masculino , Mutação , Estudos Retrospectivos , Análise de Sequência de DNA
3.
Rinsho Ketsueki ; 60(9): 1337-1340, 2019.
Artigo em Japonês | MEDLINE | ID: mdl-31597861

RESUMO

Various types of infectious complications could develop after allogeneic hematopoietic stem cell transplantation (HSCT) due to the associated intensive immunosuppression. Cellular immunity is also impaired, resulting in a higher incidence of viral infections when compared with standard chemotherapy. Cytomegalovirus (CMV) reactivates in seropositive patients under immunosuppression after allogeneic HSCT, causing complications, such as pneumonitis, gastroenteritis, and retinitis. Because intervention before the onset of disease, rather than after, can improve prognosis, preemptive therapy guided by early detection of CMV reactivation has been extensively used. Recently, the introduction of a less myelotoxic agent, letermovir, has enabled prophylactic therapy to be administered safely and effectively. In addition, prophylactic letermovir is expected to reduce transplant-related mortality. However, the onset of CMV infection/disease as either a breakthrough infection or after the discontinuation of letermovir is still problematic. In this section, the management tips for CMV infection after allogeneic HSCT have been summarized.


Assuntos
Acetatos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Citomegalovirus/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Quinazolinas/uso terapêutico , Citomegalovirus , Infecções por Citomegalovirus/etiologia , Humanos , Incidência
4.
Mol Med Rep ; 20(4): 3625-3632, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485668

RESUMO

The aim of this study was to explore the synergistic effect of signal transducer and activator of transcription 3 (STAT3)­targeted small interfering (si)RNA and AZD0530 against glioblastoma in vitro and in vivo. Glioblastoma cell lines U87 and U251 were divided into four groups and treated with control, LV­STAT3 siRNA, AZD0530, and combined LV­STAT3 siRNA with AZD0530, respectively. The proliferation and apoptotic capacity of glioblastoma cells was assessed by Cell Counting Kit­8 and double staining flow cytometry assays, respectively. Additionally, the potential effect of LV­STAT3 siRNA and AZD0530 on glioblastoma was evaluated in vivo. Images were captured of the tumor formation in mice every week. Following three weeks of treatment, NMR scan and immunohistochemistry were performed. The treatment of combined LV­STAT3 siRNA and AZD0530 was more effective in inhibiting proliferation and inducing apoptosisof glioblastoma cells in comparison with the treatment of either LV­STAT3 siRNA or AZD0530 alone. Although LV­STAT3 siRNA or AZD0530 treatment alone suppressed tumor growth in mice, the combined treatment had a more significant effect than the treatment of LV­STAT3 siRNA or AZD0530 alone. According to the results of both in vitro and in vivo assays, a combined therapy of LV­STAT3 siRNA with AZD0530 could enhance therapeutic effects on glioblastoma, supporting the idea that the combination of LV­STAT3 siRNA and AZD0530 could serve as a novel and effective strategy to combat glioblastoma.


Assuntos
Antineoplásicos/uso terapêutico , Benzodioxóis/uso terapêutico , Neoplasias Encefálicas/terapia , Glioblastoma/terapia , Quinazolinas/uso terapêutico , Terapêutica com RNAi , Fator de Transcrição STAT3/genética , Animais , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Terapia Combinada/métodos , Glioblastoma/genética , Glioblastoma/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , RNA Interferente Pequeno/uso terapêutico , Terapêutica com RNAi/métodos
5.
Biomed Pharmacother ; 117: 109185, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31387179

RESUMO

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) is the first-line treatment in non-resectable non-small lung cancer (NSCLC) with EGFR mutation. However, EGFR-TIKs resistance would inevitably develop within 9-14 months after treatment. And, chemotherapy is the main treatment for EGFR-TKIs resistant patients. WEE1 kinase, a G2/M checkpoint regulator, was recently considered as a putative biomarker for the platinum-based chemo-response. The aim of this study is to clarify the relationship between WEE1 kinase and chemosensitivity in EGFR-TKIs resistant NSCLC. WEE1 expression was tested in EGFR-TKIs resistant cell lines (H1299, PC9/G2) and patients' specimens by western blot, qPCR and immunohistochemistry (IHC). In in vitro experiment, WEE1 expression was higher in EGFR-TKIs resistant than EGFR-TKIs sensitive cell lines and was gradually increased following cisplatin or gemcitabine treatment with the enrichment of G2/M cell cycle phase. And, for patients with acquired Icotinib/Gefitinib resistance, 58.4% (7/12) had increased WEE1 expression compared to its initial expression level. In order to explore the impact of WEE1 on chemo-response, WEE1 knockdown was conducted in EGFR-TKIs resistant H1299 and PC9/G2 cells. MTT and colony formation assay showed that the efficacy of cisplatin and gemcitabine was enhanced in the two cell lines after WEE1 knockdown. And, the IC50 value of cisplatin decreased from 8.64 µg/ml to 3.10 µg/ml or 2.38 µg/ml in H1299 and from 3.66 µg/ml to 0.97 µg/ml or 1.18 µg/ml in PC9/G2 after WEE1 knockdown with two specific shRNAs. This study revealed that WEE1 expression was increased after EGFR-TKIs resistance, and WEE1 knockdown could enhance chemosensitivity in EGFR-TKIs resistant NSCLC. It is suggested the combination of WEE1 inhibitor and chemotherapy might improve the clinical outcome of NSCLC patients with acquired EGFR-TKIs resistance.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Proteínas de Ciclo Celular/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Proteínas Tirosina Quinases/antagonistas & inibidores , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Éteres de Coroa/uso terapêutico , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Receptores ErbB/metabolismo , Feminino , Pontos de Checagem da Fase G2 do Ciclo Celular/efeitos dos fármacos , Gefitinibe/uso terapêutico , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Quinazolinas/uso terapêutico , RNA Interferente Pequeno/metabolismo
6.
Medicine (Baltimore) ; 98(31): e16392, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374006

RESUMO

RATIONALE: Vandetanib is effective for treating symptomatic or progressive medullary thyroid cancer (MTC) in patients with unresectable locally advanced or metastatic disease, but its toxicity such as photosensitivity reactions should be considered. It is a rare adverse effect of this drug but might cause severe morbidity and even mortality. PATIENT CONCERNS: A 26-year man with MTC developed phototoxic rashes on the sun-exposed areas of his shin after 15 days from the initiation of vandetanib treatment. Grade II skin toxicity was evaluated based on the Common Terminology Criteria for Adverse Events standard. DIAGNOSES: Drug-induced phototoxic rash. INTERVENTIONS: The vandetanib dose was reduced by 30%, and the application of topical steroids and sunscreen was adopted. OUTCOMES: After dose reduction of vandetanib, the symptoms of vandetanib-induced phototoxic rash resolved, although residual pigmentation was observed. LESSONS: Close attention should be paid to the adverse effect of vandetanib, phototoxic rash, and patients should be advised on the prevention and treatment measures.


Assuntos
Dermatite Fototóxica/etiologia , Piperidinas/efeitos adversos , Quinazolinas/efeitos adversos , Neoplasias da Glândula Tireoide/tratamento farmacológico , Adulto , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Humanos , Masculino , Piperidinas/uso terapêutico , Quinazolinas/uso terapêutico
7.
Cancer Sci ; 110(11): 3442-3452, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31432592

RESUMO

Functional E-cadherin loss, a hallmark of epithelial-mesenchymal transition (EMT), is important for metastasis. However, the mechanism of Snail2 in hepatocellular carcinoma (HCC) EMT and metastasis remains unclear. Here, we showed that Snail2 was upregulated in primary HCC, and significantly increased during transforming growth factor-ß-induced liver cell EMT. Snail2-overexpressing and knockdown cell lines have been established to determine its function in EMT in HCC. H3K9 methylation was upregulated and H3K4 and H3K56 acetylation were downregulated at the E-cadherin promoter in Snail2-overexpressing cancer cells. Furthermore, Snail2 interacted with G9a and histone deacetylases (HDACs) to form a complex to suppress E-cadherin transcription. Snail2 overexpression enhanced migration and invasion in HCC cells, whereas G9a and HDAC inhibition significantly reversed this effect. Moreover, Snail2 overexpression in cancer cells increased tumor metastasis and shortened survival time in mice, whereas G9a and HDAC inhibitors extended survival. Our study not only reveals a critical mechanism underlying the epigenetic regulation of EMT but also suggests novel treatment strategies for HCC.


Assuntos
Caderinas/metabolismo , Carcinoma Hepatocelular/metabolismo , Epigênese Genética , Transição Epitelial-Mesenquimal/genética , Antígenos de Histocompatibilidade/metabolismo , Histona Desacetilases/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Neoplasias Hepáticas/metabolismo , Fatores de Transcrição da Família Snail/metabolismo , Acetilação , Animais , Azepinas/uso terapêutico , Carcinoma Hepatocelular/secundário , Movimento Celular , Progressão da Doença , Regulação para Baixo , Feminino , Inibidores de Histona Desacetilases/uso terapêutico , Humanos , Ácidos Hidroxâmicos/uso terapêutico , Fígado/efeitos dos fármacos , Fígado/metabolismo , Neoplasias Hepáticas/patologia , Metilação , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Metástase Neoplásica , Quinazolinas/uso terapêutico , Transcrição Genética , Fator de Crescimento Transformador beta/farmacologia
8.
Future Oncol ; 15(22): 2571-2576, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31407939

RESUMO

Fruquintinib is a potent, highly selective and orally active inhibitor of VEGFR1, 2, 3 tyrosine kinases. It inhibits VEGF-induced VEGFR2 phosphorylation, endothelial cell proliferation and tubule formation. Currently, it has been approved for the treatment of metastatic colorectal cancer in patients who have failed at least two prior systemic antineoplastic therapies in China. However, it is not approved outside China, and there is another similar small molecular VEGFR multitarget drug approved in China, USA, Europe, etc. Here, we summarize the mechanism characteristics and clinical development of fruquintinib supporting its use in the treatment of metastastic colorectal cancer as well as explorations in other tumor types.


Assuntos
Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Quinazolinas/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/genética , Inibidores da Angiogênese/uso terapêutico , Proliferação de Células/efeitos dos fármacos , China , Ensaios Clínicos como Assunto , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Europa (Continente) , Humanos , Metástase Neoplásica , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Fosforilação/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/genética
9.
Semin Oncol ; 46(2): 145-154, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31280996

RESUMO

Malignant pleural mesothelioma (MPM) is a global health issue, the principal cause of which is exposure to asbestos. The prevalence is anticipated to rise over the next 2 decades, particularly in developing countries, due to the 30-50-year latency period between exposure to asbestos and carcinogenic development. Unresectable MPM has a poor prognosis and limited treatment options and, as such, there is a broad range of therapeutic targets of interest, including angiogenesis, immune checkpoints, mesothelin, as well as chemotherapeutic agents. Recently, the results of several randomized trials in the first-line setting combining antiangiogenic agents with chemotherapy have been reported. This review examines the scientific rationale for targeting angiogenesis in the treatment of unresectable MPM and analyzes recent clinical results with antiangiogenic agents in development (bevacizumab, nintedanib, and cediranib) for the management of MPM.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Mesotelioma/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Asbestos/toxicidade , Bevacizumab/uso terapêutico , Carcinogênese/genética , Humanos , Indóis/uso terapêutico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Mesotelioma/genética , Mesotelioma/patologia , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Neoplasias Pleurais/genética , Neoplasias Pleurais/patologia , Quinazolinas/uso terapêutico
10.
Expert Opin Pharmacother ; 20(12): 1429-1438, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31282759

RESUMO

Introduction: Human cytomegalovirus (HCMV) or human herpesvirus 5 (HHV-5) is a ß-herpesvirus that causes widespread infection in nearly all members of the human population worldwide. Its persistence in humans after primary infection in a latent phase as well as a partial non-protective immune response is the basis for repeated re-activation/re-infection episodes occurring both in immunocompetent and immunocompromised subjects. In the latter patient populations, which include hematopoietic stem cell transplant (HSCT) recipients, HCMV reactivation episodes may be particularly severe, leading to both systemic and end-organ diseases. Since the 90s, at least four antiviral drugs targeting the DNA polymerase complex have been developed for the prevention and treatment of HCMV infections in transplant recipients, used as first-line (ganciclovir and valganciclovir) and second-line therapy (foscarnet and cidofovir). However, due to their toxicity and drug-resistance induction, new drugs with different targets were needed. Areas covered: In 2017, a new drug named letermovir (LTV), which targets the HCMV DNA terminase complex, was licensed for prophylaxis of HCMV infections in HSCT recipients. This is the focus of this review. Expert opinion: LTV safety and efficacy are promising. However, long-term adverse events and the emergence of drug-resistant HCMV strains must be investigated in extended clinical trials prior to drawing final conclusions.


Assuntos
Acetatos/uso terapêutico , Quimioprevenção/métodos , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/efeitos dos fármacos , Quinazolinas/uso terapêutico , Antivirais/uso terapêutico , Quimioprevenção/estatística & dados numéricos , Cidofovir/uso terapêutico , Citomegalovirus/genética , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/epidemiologia , Farmacorresistência Viral/efeitos dos fármacos , Ganciclovir/uso terapêutico , Humanos , Hospedeiro Imunocomprometido/efeitos dos fármacos , Transplantados/estatística & dados numéricos , Condicionamento Pré-Transplante/métodos , Condicionamento Pré-Transplante/estatística & dados numéricos , Valganciclovir/uso terapêutico
11.
J Cancer Res Clin Oncol ; 145(9): 2313-2323, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31278474

RESUMO

BACKGROUND: The optimal treatment in the third-line and later-line setting for metastatic colorectal cancer (mCRC) has not been established. As reported, regorafenib and fruquintinib have shown to be superior to placebo in mCRC. However, no direct clinical comparison of regorafenib and fruquintinib has been conducted; we performed a systematic review and network meta-analysis to compare the efficacy and safety of regorafenib and fruquintinib. METHODS: PubMed, Embase, and the Cochrane Library were systematically searched and randomized-controlled trials (RCTs) assessing the effect and safety of regorafenib or fruquintinib versus placebo for patients with mCRC were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. After that, we performed pairwise direct meta-analyses (regorafenib vs. placebo and fruquintinib vs. placebo) and indirect comparison (regorafenib vs. fruquintinib) using network meta-analyses methods. RESULTS: Three RCTs involving 1380 patients were included in the meta-analysis. In the direct meta-analysis, regorafenib and fruquintinib both showed survival benefits when compared with placebo. For the indirect comparison, fruquintinib shows no significant difference in OS compared to regorafenib (HR 0.97; 95% CI 0.64-1.46). Regarding PFS, there was a tendency that fruquintinib was superior to regorafenib (HR 0.65; 95% CI 0.39-1.08); however, there was no statistic difference. For the safety analysis, in indirect comparison, fruquintinib showed significant difference in all-grade toxicity compared to regorafenib (OR 0.73; 95% CI 0.65-0.82), especially in subgroup of proteinuria (OR 0.31; 95% CI 0.11-0.86). For the grade 3-5 toxicity, fruquintinib showed no significant difference when compared with regorafenib (OR 0.92; 95% CI 0.64-1.32). CONCLUSION: Based on efficacy and safety, there was a tendency that fruquintinib was superior to regorafenib, as a whole, regorafenib and fruquintinib demonstrated similar clinical benefit for patients with refractory mCRC. It seems that fruquintinib has less toxic in all-grade toxicity when compared with regorafenib.


Assuntos
Benzofuranos/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Compostos de Fenilureia/uso terapêutico , Piridinas/uso terapêutico , Quinazolinas/uso terapêutico , Neoplasias Colorretais/epidemiologia , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Meta-Análise em Rede , Resultado do Tratamento
12.
Nanoscale ; 11(29): 13947-13960, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31305836

RESUMO

Combined modality therapy incorporating raltitrexed (RTX), a thymidylate synthase inhibitor, and radiation can lead to improved outcome for rectal cancer patients. To increase delivery and treatment efficacy, we formulated a hyaluronic acid (HA) coated nanoparticle encapsulating RTX (HARPs) through layer-by-layer assembly. These particles were determined to have a diameter of ∼115 nm, with a polydispersity index of 0.112 and a zeta potential of -22 mV. Cell uptake in CT26 cells determined through flow cytometry showed a ∼5-fold increase between untargeted and HA-coated particles. Through viability and DNA damage assays, we assessed the potency of the free RTX and HARPs, and found increased DNA damage in cells treated with the RTX-loaded nanoparticles administered concurrently with radiation. In vivo efficacy through tumor growth inhibition was investigated in a syngeneic murine colorectal cancer model. Nanoparticle treatment showed no acute toxicity in vivo, and all treatments showed survival benefits for their respective groups compared to controls. HARPs alone slowed tumor growth, although not significantly. Radiation alone and in combination with the HARPs showed significant growth delay. Notably, the combination treatment significantly hindered tumor progression relative to the HARPs highlighting the benefit of this multipronged treatment. These results provide a foundation for loading RTX in a nanoparticle formulation, and establish a combined radiation and drug dosing schedule to determine optimal tumor growth delay and subsequent treatment efficacy.


Assuntos
Antimetabólitos Antineoplásicos/química , Portadores de Fármacos/química , Ácido Hialurônico/química , Nanopartículas/química , Quinazolinas/química , Tiofenos/química , Animais , Antimetabólitos Antineoplásicos/farmacologia , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Neoplasias Colorretais/radioterapia , Dano ao DNA/efeitos dos fármacos , Portadores de Fármacos/metabolismo , Histonas/metabolismo , Humanos , Estimativa de Kaplan-Meier , Fígado/efeitos dos fármacos , Fígado/patologia , Camundongos , Camundongos Endogâmicos BALB C , Nanopartículas/metabolismo , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Radiação Ionizante , Tiofenos/farmacologia , Tiofenos/uso terapêutico , Transplante Heterólogo
13.
Jpn J Clin Oncol ; 49(8): 786-788, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31187861

RESUMO

Exon 18 delE709_T710insD is an extremely rare mutation in epidermal growth factor receptor (EGFR) in non-small-cell lung cancer (NSCLC); the efficacy of EGFR tyrosine kinase inhibitors against this mutation remains unclear. In this case report, we report a case of NSCLC harboring EGFR exon 18 delE709_T710insD that was not detected by a commercially available assay, but was detected by a next-generation sequencing cancer panel. A 56-year old female patient with advanced NSCLC was diagnosed as EGFR-mutation-negative using the PNAClamp method. ALK rearrangement was also absent and she received cytotoxic chemotherapies. Clinical characteristics, including adenocarcinoma histology and no history of smoking, implied the presence of a driver mutation, so a next-generation-sequencing Oncomine® Cancer Research Panel was conducted in the patient's clinical course and the EGFR exon 18 delE709_T710insD mutation was detected. The patient started afatinib as sixth-line treatment and her pulmonary lesion significantly decreased in size. Afatinib was continued for 7 months until disease progressed.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/genética , Afatinib/uso terapêutico , Éxons/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Mutação/genética , Adenocarcinoma de Pulmão/diagnóstico por imagem , Idoso , Receptores ErbB/genética , Feminino , Humanos , Neoplasias Pulmonares/diagnóstico por imagem , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/uso terapêutico , Quinazolinas/uso terapêutico , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
PLoS One ; 14(6): e0216463, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31185023

RESUMO

Schizophrenia has been consistently characterized by abnormal patterns of gene down-regulation, increased restrictive chromatin assemblies, and reduced transcriptional activity. Histone methyltransferase (HMT) mRNA and H3K9me2 levels are elevated in postmortem brain and peripheral blood cells of persons with schizophrenia. Moreover, this epigenomic state likely contributes to the disease, as HMT levels correlate with clinical symptomatology. This manuscript sought to establish the potential therapeutic value of the HMT inhibitor BIX-01294 (BIX). Human peripheral mononuclear cells (PBMC) from 24 individuals with schizophrenia and 24 healthy individuals were cultured in the presence of BIX (5uM or 10uM). Mice were given once daily intraperitoneal injections of BIX (0.5 or 1mg/kg) for one week. Cultured cells, mouse cortex, or striatum was harvested, RNA extracted and RT-PCR conducted for several schizophrenia candidate genes: IL-6, Gad1, Nanog, KLF4, Reln, and Bdnf9a. Total H3K9me2 levels were measured using western blot while H3K9me2 binding to selected genes of interest was conducted using chromatin immunoprecipitation (ChIP). Neuronal subtype-specific BDNF conditional knockdown was conducted using the cre/lox system of mutant animals. Treatment with BIX decreased H3K9me2 and increased selected mRNA levels in cultured PBMCs from both normal controls and participants with schizophrenia. In mice, peripheral administration of BIX decreased cortical H3K9me2 levels and increased schizophrenia candidate gene expression. In BDNF conditional knockdown animals, BIX administration was able to significantly rescue Bdnf9a mRNA levels in ChAT and D1 Bdnf conditional knockdown mice. The results presented in this manuscript demonstrate a potential for further research into the clinical effectiveness of histone modifying pharmacology in the treatment of schizophrenia.


Assuntos
Azepinas/farmacologia , Inibidores Enzimáticos/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Código das Histonas/efeitos dos fármacos , Histona Metiltransferases/antagonistas & inibidores , Quinazolinas/farmacologia , Animais , Azepinas/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/genética , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Inibidores Enzimáticos/uso terapêutico , Feminino , Histonas/metabolismo , Humanos , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Mutação , Quinazolinas/uso terapêutico , RNA Mensageiro/genética , Esquizofrenia/sangue , Esquizofrenia/tratamento farmacológico , Esquizofrenia/genética
15.
Crit Rev Oncol Hematol ; 140: 17-27, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154235

RESUMO

Metastasis leads to poor prognosis and reduced disease-free survival in breast cancer patients, particularly in those with triple-negative breast cancer (TNBC) which is resistant to common treatments. Anoikis is a type of apoptosis commenced by the detachment of cells from the native extracellular matrix and prohibits the attachment of detached cells to other body organs. Resistance to anoikis is a critical culprit in the development and progression of tumours. It is therefore important to understand the anoikis-related molecular pathways in order to design effective therapies for TNBC. Several compounds have been shown to possess the potential to regulate anoikis in breast cancer cells such as DSF, AEB071, nanoencapsulated doxorubicin, berberine, salinomycin, PEM POL5551, AL10, 5-azacytidine, synthesized flavonoid derivative GL-V9, Tubeimoside V (TBMS-V) and HPW-RX40. We reviewed the molecular basis of anoikis regulation, its potential role as an important target to inhibit metastasis in TNBC, and potential anoikis modulators that could serve as drug candidates.


Assuntos
Anoikis , Regulação Neoplásica da Expressão Gênica , Transdução de Sinais , Neoplasias de Mama Triplo Negativas/fisiopatologia , Berberina/farmacologia , Berberina/uso terapêutico , Clorobenzoatos/farmacologia , Clorobenzoatos/uso terapêutico , Feminino , Humanos , Piranos/farmacologia , Piranos/uso terapêutico , Pirróis/farmacologia , Pirróis/uso terapêutico , Quinazolinas/farmacologia , Quinazolinas/uso terapêutico , Saponinas/farmacologia , Saponinas/uso terapêutico , Estirenos/farmacologia , Estirenos/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo
16.
Eur J Haematol ; 103(2): 116-123, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31107982

RESUMO

OBJECTIVE: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting. METHOD: Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. RESULTS: The rate of achieving a platelet count of <600 × 109 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. CONCLUSION: In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.


Assuntos
Inibidores da Agregação de Plaquetas/uso terapêutico , Quinazolinas/uso terapêutico , Trombocitemia Essencial/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Progressão da Doença , Quimioterapia Combinada , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Contagem de Plaquetas , Fatores de Risco , Trombocitemia Essencial/sangue , Trombocitemia Essencial/diagnóstico , Trombocitemia Essencial/etiologia , Resultado do Tratamento , Adulto Jovem
17.
Integr Cancer Ther ; 18: 1534735419842373, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31043093

RESUMO

OBJECTIVE: To examine the effects of a wellness-education intervention on quality of life (QOL) of patients with NSCLC treated with icotinib and on their caregivers. METHODS: This feasibility study was a prospective pilot randomized controlled trial to evaluate a wellness-education intervention in NSCLC patients and caregivers undergoing icotinib treatment. The participants in the wellness-education group were provided with well-being information over 8 weeks. The Family Environment Scale (FES), Functional Assessment of Cancer Therapy-Lung (FACT-L), Caregiver QOL Index-Cancer Scale (CQOLC), and Hospital Anxiety and Depression Scale (HADS) were measured at baseline prior to randomization and after 8 weeks. Patients completed the FACT-L and HADS, caregivers completed the CQOLC and FES. RESULTS: 67 patients/caregivers in the wellness-education group and 71 in the control group could be analyzed. Feasibility targets were the following: (1) >70% study enrollment of eligible patients; (2) >90% of participants completing this study; (3) <10% missing data. Wellness-education group had better change scores at 8 weeks for the emotional well-being subscale of FACT-L (12.8 vs 15.6, P = .014), anxiety subscale of HADS (6.1 vs 6.7, P = .030), adaptation (66.0 vs 54.7, P = .037) and financial subscales of CQOLC (70.8 vs 69.8, P = .044), and the cohesion (7.3 ± 1.8 vs 5.7 ± 1.7, P= .021) and conflict (3.4 ± 1.9 vs 4.5 ± 1.7, P = .031) subscales of the FES. CONCLUSION: Wellness-education in patients/caregivers with NSCLC treated with icotinib are feasible and could improve patients' QOL and their relationship with caregivers.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/psicologia , Cuidadores/psicologia , Éteres de Coroa/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/psicologia , Qualidade de Vida/psicologia , Quinazolinas/uso terapêutico , Adaptação Psicológica/fisiologia , Ansiedade/psicologia , Depressão/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Estresse Psicológico/psicologia , Inquéritos e Questionários
18.
BMC Infect Dis ; 19(1): 388, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31068147

RESUMO

BACKGROUND: The compound letermovir (LMV) has recently been approved for the prophylaxis of cytomegalovirus (CMV) infection and disease in adult CMV seropositive recipients of an allogeneic hematopoietic stem cell transplant. LMV inhibits CMV replication by binding to the viral terminase complex. However, first cases of clinical LMV resistance have been occurred. Here we report a fast breakthrough of resistant cytomegalovirus during secondary LMV prophylaxis in a hematopoietic-cell transplant recipient. CASE PRESENTATION: A 44-year-old male patient with acute myeloid leukemia (AML) experienced a CMV-reactivation within the first 4 weeks of allogeneic hematopoietic-cell transplantation. Administration of LMV was initiated at day + 34. Due to increasing viral loads, LMV treatment was discontinued after 8 days. The patient was then administered with valganciclovir (valGCV) until viral DNA was undetectable. Due to neutropenia, valGCV treatment was switched to LMV secondary prophylaxis. For 4 weeks, the patient maintain virologic suppression. Then, CMV viral loads increased with a fast kinetic. Genotypic testing of the viral polymerase UL54, the kinase UL97 as well as the viral terminase UL56 and UL89 revealed the mutation C325Y in UL56, which is associated with the high level LMV resistance. CONCLUSION: It is known that Letermovir is approved for prophylactic purposes. However, it may be used for some patients with CMV infection who either have failed prior therapies or are unable to tolerate other anti-CMV compounds. Particularly, the administration of LMV should be avoided in patients with detectable viral loads. When this is not possible, viral load must be routinely monitored along with UL56 genotyping. Furthermore, LMV administration at high virus loads may foster the rapid selection of resistant CMV mutants.


Assuntos
Acetatos/uso terapêutico , Antivirais/uso terapêutico , Infecções por Citomegalovirus/prevenção & controle , Citomegalovirus/efeitos dos fármacos , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Quinazolinas/uso terapêutico , Adulto , Citomegalovirus/genética , Infecções por Citomegalovirus/tratamento farmacológico , Infecções por Citomegalovirus/virologia , DNA Polimerase Dirigida por DNA/genética , Farmacorresistência Viral/efeitos dos fármacos , Humanos , Masculino , Mutação , Prevenção Secundária , Valganciclovir/uso terapêutico , Carga Viral/efeitos dos fármacos , Proteínas Virais/genética , Proteínas Estruturais Virais/genética
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