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1.
Radiol Med ; 125(1): 98-106, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31583558

RESUMO

PURPOSE: To evaluate safety and efficacy of degradable starch microspheres (DSMs) TACE in a large clinical cohort of patients with unresectable HCC. MATERIALS AND METHODS: This is a single-center consecutive patients cohort study. The study was approved by local institutional ethics committee. Written informed consent was obtained. From December 2013 to March 2018, 137 cirrhotic patients with unresectable HCC were enrolled. For DSMs-TACE, a mixture of 4 mL of DSMs, 6 mL of non-ionic contrast and doxorubicin at a dose of 50 mg/m2 were used. Primary end point was long-term outcome, in terms of time to progression (TTP) and overall survival (OS). Secondary endpoints were: safety, liver toxicity, 1-month percentage of tumor necrosis according to the modified RECIST criteria. RESULTS: Two hundred and sixty-seven DSMs-TACE were performed in 137 HCC patients (33 patients in BCLC stage A, 84 patients in BCLC stage B, and 20 in stage C). Patients had a mean nodule number of 3.5 ± 1.2 (SD). Major complications were observed in 6.8% of cases. Post-embolization syndrome was common (101 patients 73.7%). According to mRecist criteria, a high objective response rate was obtained even after just one treatment (84.3% of patients showed complete response or partial response). The median TTP and OS after DSMs-TACE were 12 months and 36 months, respectively. OS at 6 months, 1 year, 2 and 3 years was 98%, 81.3%, 57.9%, 34.9%, respectively. CONCLUSION: DSMs-TACE is a safe and effective therapy for patients with HCC, allowing to obtain a good rate of OS with excellent local tumor control.


Assuntos
Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Neoplasias Hepáticas/terapia , Amido/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Quimioembolização Terapêutica/efeitos adversos , Quimioembolização Terapêutica/mortalidade , Doxorrubicina/administração & dosagem , Feminino , Humanos , Cirrose Hepática/complicações , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Critérios de Avaliação de Resposta em Tumores Sólidos , Retratamento/estatística & dados numéricos , Amido/efeitos adversos , Tomografia Computadorizada por Raios X , Resultado do Tratamento
2.
Life Sci ; 241: 117154, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31857087

RESUMO

AIM: Insulin resistance and neuroinflammation play roles in Alzheimer's (AD) etiology. Insulin receptors (IR) are developmentally expressed in neurons as well as astrocytes. Moreover, prolonged stress can induce brain insulin resistance and astrogliosis. Also, prenatal stress could advance AD-related abnormalities in a transgenic model of AD. Besides, postnatal maternal care (PMC) has antagonistic effects on prenatal stress (PS)-induced neuronal and immunological malfunctions. Using an icv-STZ subclinical model of sAD, we assessed PS and/or abnormal PMC impacts on advancing sAD-like pathology in adult male rats. We also sought astrocyte- and/or neuron-oriented change in central insulin programming. MAIN METHODS: Pregnant rats were exposed to PS. Thereafter, a group of pups was fostered onto unstressed mothers and the others remained intact. Real-time RT-PCR- for hippocampal IR, Tau, and ChAT transcripts- and immunohistochemistry analysis- for GFAP+ astrocytes- were performed at the first- and forth-postnatal-week, respectively. The other animals received icv-STZ0.5 mg/kg in adulthood and subjected to cognitive tests, molecular, and histological experiments at appropriate time-point post-injection. KEY FINDINGS: PS could advance sAD-related symptoms in icv-STZ-treated animals. PS changed expression levels of hippocampal IR in one-week-old and 5.5-month-old offspring. PS could worsen cognitive, molecular and histological impairments of icv-STZ. Adequate PMC prevented some destructive effects of PS. SIGNIFICANCE: PS can potentially change central insulin programming and induce long-lasting astrogliosis in rat hippocampus. PS-related cognitive and histological pathologies can rescue by PMC probably via IR-dependent pathways. Astrocyte involvement in AD-like neuropathology observed in stressed-animals needs more detailed investigations.


Assuntos
Doença de Alzheimer/patologia , Comportamento Animal , Modelos Animais de Doenças , Resistência à Insulina , Efeitos Tardios da Exposição Pré-Natal/fisiopatologia , Estreptozocina/toxicidade , Estresse Psicológico/complicações , Doença de Alzheimer/etiologia , Doença de Alzheimer/metabolismo , Animais , Animais Recém-Nascidos , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/toxicidade , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Feminino , Infusões Intraventriculares , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurônios/patologia , Gravidez , Ratos , Ratos Wistar , Receptor de Insulina/metabolismo , Transdução de Sinais , Estreptozocina/administração & dosagem
3.
Urol Clin North Am ; 47(1): 55-72, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31757301

RESUMO

Non-muscle-invasive bladder cancer can be a challenging disease to manage. In recent years, hyperthermia therapy in conjunction with intravesical therapy has been gaining traction as a treatment option for bladder cancer, especially if Bacillus Calmette-Guerin might not be available. Trials of intravesical chemotherapy with heat are few and there has been considerable heterogeneity between studies. However, multiple new trials have accrued and high-quality data are forthcoming. In this review, we discuss the role of combined intravesical hyperthermia and chemotherapy as a novel approach for the treatment of bladder cancer.


Assuntos
Hipertermia Induzida/métodos , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/terapia , Administração Intravesical , Antibióticos Antineoplásicos/administração & dosagem , Humanos , Resultado do Tratamento
4.
Braz J Med Biol Res ; 52(12): e8467, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31800729

RESUMO

The aim of our study was to assess the efficacy, safety, and prognostic factors of drug-eluting bead transarterial chemoembolization (DEB-TACE) in Chinese hepatocellular carcinoma (HCC) patients. Patients (n=102) diagnosed as primary HCC were consecutively enrolled in this retrospective cohort study. Treatment responses were assessed following the modified Response Evaluation Criteria in Solid Tumors. Progression-free survival (PFS) and overall survival (OS) were evaluated, and adverse events (AEs) as well as liver function-related laboratory indexes of all DEB-TACE records (N=131) were assessed. Complete response (CR) rate, objective response rate, and disease control rate were 51.0, 87.3, and 95.1%, respectively, at 1-3 months post DEB-TACE. The mean PFS and OS were 227 (95%CI: 200-255) days and 343 (95%CI: 309-377) days, respectively. Multivariate logistic regression revealed that portal vein invasion and abnormal total protein (TP) were independent predictive factors for worse CR, and multivariate Cox's regression analysis showed that multifocal disease independently correlated with shorter PFS. Most of the liver function-related laboratory indexes worsened at 1 week but recovered at 1-3 months post-treatment, only the percentage of patients with abnormal ALP increased at 1-3 months. In addition, 112 (85.5%), 84 (64.1%), 53 (40.5%), 40 (30.5%), and 16 (12.2%) patients had pain, fever, nausea, vomiting, and other AEs, respectively. DEB-TACE is efficient and safe in Chinese HCC patients, and portal vein invasion, abnormal TP level as well as multifocal disease could be used as unfavorable prognostic factors to DEB-TACE treatment.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/terapia , Quimioembolização Terapêutica/métodos , Epirubicina/administração & dosagem , Neoplasias Hepáticas/terapia , Idoso , Estudos de Coortes , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento
5.
Hematol Oncol ; 37(5): 569-577, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674027

RESUMO

Romidepsin is a class I selective histone deacetylase (HDAC) inhibitor approved by the Food and Drug Administration (FDA) for relapsed/refractory (R/R) cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), treated with at least one prior systemic therapy. Currently, there is paucity of real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. This national, multicenter study presents real-life data on the efficacy and safety of romidepsin in R/R T-cell lymphoma. Patients diagnosed and treated with romidepsin for R/R CTCL or PTCL between 2013 and 2018 were retrospectively reviewed. Outcomes included overall survival (OS), event-free survival (EFS), overall response rate (ORR), complete response (CR), and adverse events. Fifty-three patients with R/R PTCL (n = 42) or CTCL (n = 11) were included. Among CTCL patients, median OS was not reached, ORR was 25%, and none achieved CR. Among PTCL patients, median OS was 7.1 months, EFS was 1.9 months, ORR rate was 33%, and 12.5% achieved CR. In a univariate analysis, predictors for longer EFS include any response to therapy, number of previous lines, and PTCL subclass (with better results for angioimmunobalstic T-cell lymphoma). In a univariate and multivariate analysis for OS, treatment response was the only factor predicting OS (OR 4.48; CI 95%, 1.57-12.79; P = .005). Most grade 3 and 4 adverse events were hematological (35%). Infections were reported in 34% of patients. This real-life experience with romidepsin confirms the results of the pivotal phase II trials. PTCL subtype and the number of previous lines of therapy have an impact on EFS. In addition, patients who had good response to romidepsin benefited most in terms of both EFS and OS. Efforts should be done to identify those patients.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma Cutâneo de Células T/tratamento farmacológico , Linfoma de Células T Periférico/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Resistencia a Medicamentos Antineoplásicos , Feminino , Humanos , Estimativa de Kaplan-Meier , Linfoma Cutâneo de Células T/mortalidade , Linfoma Cutâneo de Células T/patologia , Linfoma de Células T Periférico/mortalidade , Linfoma de Células T Periférico/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Recidiva , Retratamento , Resultado do Tratamento
6.
AAPS PharmSciTech ; 21(1): 5, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31749020

RESUMO

As a synthetic clay material, laponite RDS (LR) was investigated as an effective drug carrier as a result of the special nanodisk structure together with the negative-charged surface to achieve enhanced cellular uptake and targeted delivery. In this research work, the synthesized oligomeric hyaluronic acid-aminophenylboronic acid (oHA-APBA) was entangled onto LR nanodisks to fabricate a valid targeted platform for breast cancer therapy. Briefly, through the formation of amide bonds, 3-APBA was connected to the chain of oHA with a substituted ratio of 4.0 ± 0.2% to synthesize oHA-APBA copolymer. Thereafter, doxorubicin (DOX) was inserted into the interlayer space of LR by the way of the ion exchange process, followed by an assembly with oHA-APBA as a targeted protection layer. The satisfactory drug encapsulation efficiency (> 80%) and narrow size distribution were achieved. The in vitro drug release study demonstrated the release of DOX from DOX@LR/oHA-APBA was sustained and acid dependent. In addition, after fitting the drug cumulative release of DOX@LR/oHA-APBA under different pH conditions with several kinetic models, it was identified that drug release from DOX@LR/oHA-APBA nanohybrids at pH 5.0 was mainly dependent on both diffusion and ion exchange effects. However, under the condition of pH 7.4, the drug was most efficiently released by diffusion effect. Importantly, DOX@LR/oHA-APBA showed remarkable cellular uptake and intracellular drug distribution in MCF-7 cells, which were consistent with inhibitory ability against MCF-7 cells. Hence, the high DOX loading capacity and enhanced cellular tracking can enlighten LR/oHA-APBA as an effective drug delivery carrier for breast cancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacologia , Antibióticos Antineoplásicos/química , Ácidos Borônicos , Sobrevivência Celular , Doxorrubicina/química , Portadores de Fármacos/química , Composição de Medicamentos , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Ácido Hialurônico , Concentração de Íons de Hidrogênio , Cinética , Células MCF-7 , Nanoestruturas , Silicatos
7.
Gynecol Oncol ; 155(2): 301-304, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31575390

RESUMO

OBJECTIVE: Pegylated liposomal doxorubicin (PLD) has similar reported clinical efficacy compared with conventional doxorubicin with less cardiotoxicity. The manufacturer of PLD advises that cardiac function should be evaluated with endomyocardial biopsy, echocardiography or multigated radionucleotide scan (MUGA) pre-treatment and during therapy. This study was designed to assess the necessity of pre-treatment cardiac evaluation in patients receiving PLD. METHODS: After IRB approval, a retrospective study of all women with gynecologic cancer who received PLD from 2006 to 2018 was performed. Demographic information, treatment records, cardiac risk factors, and cardiac surveillance testing were examined. Wilcoxon signed rank sum test and logistic regression were used to evaluate the association of cumulative PLD exposure with cardiotoxicity. RESULTS: A total of 235 patients received PLD for gynecologic cancer. Patients received a median of 3 cycles of PLD with a cumulative dosage of 237 mg over a median follow-up time of 24 months. Sixteen patients in the cohort (7%) had no cardiac surveillance at all. Of the remaining patients who underwent cardiac testing, 183 (84%) received MUGA scans and 36 (16%) had echocardiography. Of the 56 patients who had both pre- and post-treatment cardiac testing, there was no significant difference in median ejection fraction (p = 0.17). Three patients developed PLD-associated cardiac toxicity but only one patient had severe manifestations requiring discontinuation of PLD therapy. CONCLUSIONS: Routine cardiac testing before, during or after treatment with PLD may be unnecessary. Cardiac testing may be more appropriate for individual patients for whom the clinical suspicion of PLD-related cardiac toxicity is high.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/análogos & derivados , Neoplasias dos Genitais Femininos/tratamento farmacológico , Cardiopatias/induzido quimicamente , Doxorrubicina/efeitos adversos , Substituição de Medicamentos , Ecocardiografia/métodos , Feminino , Cardiopatias/fisiopatologia , Cardiopatias/prevenção & controle , Humanos , Pessoa de Meia-Idade , Imagem Multimodal/métodos , Polietilenoglicóis/efeitos adversos , Angiografia Cintilográfica/métodos , Estudos Retrospectivos , Volume Sistólico/efeitos dos fármacos
8.
Nat Commun ; 10(1): 4861, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31649241

RESUMO

Achieving the activation of drugs within cellular systems may provide targeted therapies. Here we construct a tumour-selective cascade activatable self-detained system (TCASS) and incorporate imaging probes and therapeutics. We show in different mouse models that the TCASS system accumulates in solid tumours. The molecules show enhanced accumulation in tumour regions via the effect of recognition induced self-assembly. Analysis of the molecular penetration in tumour tissue shows that in vivo self-assembly increases the penetration capability compared to typical soft or hard nanomaterials. Importantly, the in vivo self-assembled molecules exhibit a comparable clearance pathway to that of small molecules, which are excreted from organs of the reticuloendothelial system (liver and kidney), while are relatively slowly eliminated from tumour tissues. Finally, this system, combined with the NIR probe, shows high specificity and sensitivity for detecting bladder cancer in isolated intact patient bladders.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma de Células de Transição/diagnóstico por imagem , Corantes/administração & dosagem , Sistemas de Liberação de Medicamentos , Engenharia de Proteínas/métodos , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Motivos de Aminoácidos , Animais , Disponibilidade Biológica , Carbocianinas/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Células HEK293 , Humanos , Rim/metabolismo , Fígado/metabolismo , Camundongos , Transplante de Neoplasias , Sensibilidade e Especificidade , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Drug Deliv ; 26(1): 898-917, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31526065

RESUMO

Although intraperitoneal chemotherapy (IPC) has been suggested as a promising method for the management of peritoneal dissemination (PD) of ovarian or colorectal cancers, the actual clinical use of this method has been restricted due to such problems as poor drug penetration into the tumor and high side effects. It is, therefore, necessary to develop new strategies to improve the efficacy of this approach. In the present work, a new strategy is proposed based on intraperitoneal (IP) injection of thermosensitive liposomal doxorubicin (TSL-Dox) with triggered release by mild hyperthermia induced by high intensity focused ultrasound (HIFU). A computational model is developed to evaluate the proposed drug delivery system. Results show an order of magnitude increase in drug penetration depth into the tumor compared to the conventional IP delivery. Furthermore, the effects of thermal conditions applied to the tumor, TSL size, tumor vessel permeability, and tumor size are investigated. Results indicate an improved efficiency of the drug delivery by expanding the heated region, yet, it increases the risk of unintentional TSL drug load release in the peritoneal cavity. Results also indicate that smaller TSLs have better treatment outcome. However, there is a significant reduction in treatment efficacy for TSLs with sizes smaller than the vessel wall pore size. Thus, tuning the size of TSL should be based on the tumor microvascular permeability. The simulation results suggest that the TSL-Dox delivery system in smaller tumors is far advantageous than larger ones. Results of our model can be used as guidelines for future preclinical studies.


Assuntos
Antibióticos Antineoplásicos/química , Doxorrubicina/análogos & derivados , Lipossomos/química , Antibióticos Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos , Humanos , Hipertermia Induzida/métodos , Injeções Intraperitoneais , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Temperatura Ambiente , Distribuição Tecidual
10.
BMJ Case Rep ; 12(9)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31537597

RESUMO

AIDS-related Kaposi sarcoma (KS) is a malignancy seen in patients with HIV/AIDS that results from unrestrained human herpesvirus 8 infection. It can have an atypical presentation and an aggressive clinical course in patients with uncontrolled HIV infection. We present an interesting case of AIDS-related KS with an atypical initial presentation with skin nodules and debilitating lymphoedema. Patient was successfully managed with supportive measures, antiretroviral therapy and systemic chemotherapy.


Assuntos
Infecções Oportunistas Relacionadas com a AIDS/diagnóstico , Síndrome de Imunodeficiência Adquirida/diagnóstico , Infecções por HIV/complicações , Sarcoma de Kaposi/diagnóstico , Neoplasias Cutâneas/patologia , Infecções Oportunistas Relacionadas com a AIDS/patologia , Infecções Oportunistas Relacionadas com a AIDS/terapia , Síndrome de Imunodeficiência Adquirida/patologia , Adulto , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/patologia , Humanos , Linfedema/patologia , Masculino , Cuidados Paliativos/métodos , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/uso terapêutico , Sarcoma de Kaposi/patologia , Sarcoma de Kaposi/terapia , Resultado do Tratamento
11.
Appl Microbiol Biotechnol ; 103(20): 8559-8569, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31473797

RESUMO

Phycocyanin (PC) is a light-harvesting protein isolated from Spirulina and has health benefits for a range of diseases including pulmonary fibrosis (PF). In this study, a bleomycin-induced pulmonary fibrosis model was used to determine whether PC attenuates PF and modulates the intestinal microbiota. The results showed that PC intervention attenuated the pulmonary fibrosis, demonstrated by hematoxylin-eosin staining (HE), Masson's trichrome staining, and lung dry-wet weight ratio, and PC significantly inhibited the production of interleukin-1 beta (IL-1ß), tumor necrosis factor-α (TNF-α), and lipopolysaccharide (LPS). Additionally, intestinal microbiota analysis revealed that PC intervention significantly increased the bacterial diversity and richness. Correlation analysis indicated that 9 families and 17 genes were significantly associated with at least 1 physiological index. And PC intervention significantly decreased the bacteria which is related to inflammation and dramatically increased the SCFAs-producing bacteria and probiotics. These data indicated that PC can decrease the pro-inflammatory cytokines and regulate the intestinal microbiota in BLM-induced PF mice.


Assuntos
Antibióticos Antineoplásicos/efeitos adversos , Bleomicina/efeitos adversos , Microbioma Gastrointestinal/efeitos dos fármacos , Ficocianina/administração & dosagem , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/prevenção & controle , Animais , Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Histocitoquímica , Pulmão/patologia , Camundongos Endogâmicos C57BL , Resultado do Tratamento
12.
Radiol Med ; 124(12): 1212-1219, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31473930

RESUMO

OBJECTIVE: To evaluate the prognostic value of sequential dual-phase CBCT (DP-CBCT) imaging performed during degradable starch microsphere TACE (DSM-TACE) session in predicting the HCC's response to treatment, evaluate with modify response evaluation criteria in solid tumours (mRECIST) at 1-month multi-detector CT (MDCT) follow-up. MATERIALS AND METHODS: Between January and May 2018, 24 patients (68.5 ± 8.5 year [45-85]) with HCC lesions (n = 96 [average 4/patient]) were prospectively enrolled. Imaging assessment included: pre-procedural MDCT, intra-procedural DP-CBCT performed before first and second DSM-TACEs and 1-month follow-up MDCT. Lesions' attenuation/pseudo-attenuation was defined as average value measured on ROIs (HU for MDCT; arbitrary unit called HU* for CBCT). Lesions' attenuation modification was correlated with the post-procedural mRECIST criteria at 1-month MDCT. RESULTS: Eighty-two DSM-TACEs were performed. Lesion's attenuation values were: pre-procedural MDCT arterial phase (AP) 107.00 HU (CI 95% 100.00-115.49), venous phase (VP) 85.00 HU (CI 95% 81.13-91.74); and lesion's pseudo-attenuation were: first CBCT-AP 305.00 HU* (CI 95% 259.77-354.04), CBCT-VP 155.00 HU* (CI 95% 135.00-163.34). For second CBCT were: -AP 210.00 HU* (CI 95% 179.47-228.58), -VP 141.00 HU* (CI 95% 125.47-158.11); and for post-procedural MDCT were: -AP 95.00 HU (CI 95% 81.35-102.00), -VP 83.00 HU (CI 95% 78.00-88.00). ROC curve analysis showed that a higher difference pseudo-attenuation between first and second DP-CBCTs is related to treatment response. The optimal cut-off value of the difference between first and second CBCT-APs to predict complete response, objective response (complete + partial response) and overall disease control (objective response + stable disease) were > 206 HU* (sensitivity 80.0%, specificity 81.7%), > 72 HU* (sensitivity 79.5%, specificity 83.0%) and > - 7 HU* (sensitivity 91.6%, specificity 65.4%), respectively. CONCLUSIONS: DP-CBCT can predict intra-procedurally, by assessing lesion pseudo-attenuation modification, the DSM-TACE 1-month treatment outcome.


Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica/métodos , Tomografia Computadorizada de Feixe Cônico/métodos , Neoplasias Hepáticas , Amido/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Hepatocelular/diagnóstico por imagem , Carcinoma Hepatocelular/terapia , Epirubicina/administração & dosagem , Feminino , Humanos , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/terapia , Masculino , Microesferas , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Curva ROC , Radiografia Intervencionista/métodos , Critérios de Avaliação de Resposta em Tumores Sólidos , Sensibilidade e Especificidade , Estatísticas não Paramétricas , Fatores de Tempo , Resultado do Tratamento
13.
Blood ; 134(17): 1395-1405, 2019 10 24.
Artigo em Inglês | MEDLINE | ID: mdl-31471376

RESUMO

The peripheral T-cell lymphomas (PTCLs) are uniquely sensitive to epigenetic modifiers. Based on the synergism between histone deacetylase inhibitors and hypomethylating agents that we established in preclinical PTCL models, we conducted a phase 1 study of oral 5-azacytidine (AZA) and romidepsin (ROMI) in patients with advanced lymphoid malignancies, with emphasis on PTCL. According to a 3 + 3 design, patients were assigned to 1 of 7 cohorts with AZA doses ranging from 100 mg daily on days 1 to 14 to 300 mg daily on days 1 to 21, ROMI doses ranging from 10 mg/m2 on days 8 and 15 to 14 mg/m2 on days 8, 15, and 22, with cycles of 21 to 35 days. Coprimary end points included maximum tolerated dose (MTD) and dose-limiting toxicity (DLT). We treated a total of 31 patients. The MTD was AZA 300 mg on days 1 to 14 and ROMI 14 mg/m2 on days 8, 15, and 22 on a 35-day cycle. DLTs included grade 4 thrombocytopenia, prolonged grade 3 thrombocytopenia, grade 4 neutropenia, and pleural effusion. There were no treatment-related deaths. The combination was substantially more active in patients with PTCL than in those with non-T-cell lymphoma. The overall response rate in all, non-T-cell, and T-cell lymphoma patients was 32%, 10%, and 73%, respectively, and the complete response rates were 23%, 5%, and 55%, respectively. We did not find an association between response and level of demethylation or tumor mutational profile. This study establishes that combined epigenetic modifiers are potently active in PTCL patients. This trial was registered at www.clinicaltrials.gov as NCT01998035.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Depsipeptídeos/uso terapêutico , Linfoma de Células T/tratamento farmacológico , Adulto , Idoso , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Depsipeptídeos/administração & dosagem , Depsipeptídeos/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento , Adulto Jovem
14.
Int J Mol Sci ; 20(18)2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31509978

RESUMO

Tumorous metastasis is a difficult challenge to resolve for researchers and for clinicians. Targeted delivery of antitumor drugs towards tumor cells' nuclei can be a practical approach to resolving this issue. This work describes an efficient nuclear-targeting delivery system prepared from trans-activating transcriptional activator (TAT) peptide-functionalized graphene nanocarriers. The TAT peptide, originally observed in a human immunodeficiency virus 1 (HIV-1), was incorporated with graphene via an edge-functionalized ball-milling method developed by the author's research group. High tumor-targeting capability of the resulting nanocarrier was realized by the strong affinity between TAT and the nuclei of cancer cells, along with the enhanced permeability and retention (EPR) effect of two-dimensional graphene nanosheets. Subsequently, a common antitumor drug, mitomycin C (MMC), was covalently linked to the TAT-functionalized graphene (TG) to form a nuclear-targeted nanodrug MMC-TG. The presence of nanomaterials inside the nuclei of ocular choroidal melanoma (OCM-1) cells was shown using transmission electron microscopy (TEM) and confocal laser scanning microscopy. In vitro results from a Transwell co-culture system showed that most of the MMC-TG nanodrugs were delivered in a targeted manner to the tumorous OCM-1 cells, while a very small amount of MMC-TG was delivered in a non-targeted manner to normal human retinal pigment epithelial (ARPE-19) cells. TEM results further confirmed that apoptosis of OCM-1 cells was started from the lysis of nuclear substances, followed by the disappearance of nuclear membrane and cytoplasm. This suggests that the as-synthesized MMC-TG is a promising nuclear-target nanodrugfor resolution of tumorous metastasis issues at the headstream.


Assuntos
Neoplasias da Coroide/tratamento farmacológico , Sistemas de Liberação de Medicamentos/métodos , Grafite/química , Melanoma/tratamento farmacológico , Mitomicina/administração & dosagem , Peptídeos/química , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Linhagem Celular , Linhagem Celular Tumoral , Núcleo Celular/efeitos dos fármacos , Núcleo Celular/metabolismo , Núcleo Celular/ultraestrutura , Neoplasias da Coroide/metabolismo , Neoplasias da Coroide/patologia , Portadores de Fármacos/química , Humanos , Melanoma/metabolismo , Melanoma/patologia , Microscopia Eletrônica de Transmissão , Mitomicina/química , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Nanoestruturas/ultraestrutura , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
15.
Drug Des Devel Ther ; 13: 2043-2055, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31388296

RESUMO

Objective: To investigate the hyaluronic acid (HA) modified, doxorubicin (DOX) and gallic acid (GA) co-delivered lipid-polymeric hybrid nano-system for leukemia therapy. Methods: We produced a kind of lipid-polymer hybrid nanoparticle (LPHN) with a core-shell structure in which DOX and GA were co-loaded. In vitro and in vivo leukemia therapeutic effects of the HA modified, DOX and GA co-delivered LPHNs (HA-DOX/GA-LPHNs) were evaluated in DOX resistant human HL-60 promyelocytic leukemia cells (HL-60/ADR cells), DOX resistant human K562 chronic myeloid leukemia cells (K562/ADR cells), and HL-60/ADR cells bearing mouse model. Results: The sizes and zeta potentials of HA modified LPHNs were about 160 nm and -40 mV. HA-DOX/GA-LPHNs showed the most prominent cytotoxicity and the best synergistic effect was obtained when DOX/GA ratio was 2/1. In vivo studies revealed that HA-DOX/GA-LPHNs inhibited tumor growth from 956 mm3 to 213 mm3, with an inhibition rate of 77.7%. Conclusion: In summary, the study showed that HA-DOX/GA-LPHNs can be applied as a promising leukemia therapy system.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Ácido Gálico/farmacologia , Ácido Hialurônico/farmacologia , Leucemia Mieloide Aguda/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Gálico/administração & dosagem , Ácido Gálico/química , Células HL-60 , Humanos , Ácido Hialurônico/administração & dosagem , Ácido Hialurônico/química , Injeções Intravenosas , Células K562 , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/patologia , Lipídeos/química , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/química , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Tamanho da Partícula , Polímeros/química , Propriedades de Superfície
16.
Int J Mol Sci ; 20(16)2019 Aug 19.
Artigo em Inglês | MEDLINE | ID: mdl-31430949

RESUMO

Electrochemotherapy is an efficient method for the local treatment of cutaneous and subcutaneous metastases, but its efficacy as a systemic treatment remains low. The application of gene electrotransfer (GET) to transfer DNA coding for immune system modulating molecules could allow for a systemic effect, but its applications are limited because of possible side effects, e.g., immune system overactivation and autoimmune response. In this paper, we present the simultaneous electrotransfer of bleomycin and plasmid DNA as a method to increase the systemic effect of bleomycin-based electrochemotherapy. With appropriately selected concentrations of bleomycin and plasmid DNA, it is possible to achieve efficient cell transfection while killing cells via the cytotoxic effect of bleomycin at later time points. We also show the dynamics of both cell electrotransfection and cell death after the simultaneous electrotransfer of bleomycin and plasmid DNA. Therefore, this method could have applications in achieving the transient, cell death-controlled expression of immune system activating genes while retaining efficient bleomycin mediated cell killing.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Bleomicina/farmacologia , DNA/genética , Plasmídeos/genética , Transfecção/métodos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Bleomicina/administração & dosagem , Células CHO , Morte Celular/efeitos dos fármacos , Cricetulus , DNA/administração & dosagem , Eletroporação/métodos , Expressão Gênica/efeitos dos fármacos , Plasmídeos/administração & dosagem
17.
Biomater Sci ; 7(10): 4166-4173, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31368459

RESUMO

Metabolic glycoengineering of unnatural monosaccharides provides a facile method to label cancer cells with chemical tags for glycan imaging and cancer targeting. Multiple types of monosaccharides have been utilized for metabolic cell labeling. However, the comparison of different types of monosaccharides in labeling efficiency and selectivity has not been reported. In this study, we compared N-azidoacetylgalactosamine (GalAz) and N-azidoacetylmannosamine (ManAz) for metabolic labeling of HepG2 hepatocellular carcinoma in vitro and in vivo. GalAz showed higher labeling efficiency at low concentrations, and outperformed ManAz in metabolic labeling of HepG2 tumors in vivo. GalAz mediated labeling of HepG2 tumors with azido groups significantly improved the tumor accumulation of dibenzocyclooctyne (DBCO)-Cy5 and DBCO-doxorubicin conjugate via efficient Click chemistry. This study, for the first time, uncovered the distinct labeling efficiency and selectivity of different unnatural monosaccharides in liver cancers.


Assuntos
Azidas/administração & dosagem , Carcinoma Hepatocelular/metabolismo , Galactose/administração & dosagem , Neoplasias Hepáticas/metabolismo , Manose/administração & dosagem , Coloração e Rotulagem/métodos , Animais , Antibióticos Antineoplásicos/administração & dosagem , Azidas/farmacocinética , Radioisótopos de Carbono , Doxorrubicina/administração & dosagem , Feminino , Galactose/farmacocinética , Células Hep G2 , Humanos , Manose/farmacocinética , Engenharia Metabólica , Camundongos Nus
18.
Int J Hyperthermia ; 36(1): 817-826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31451077

RESUMO

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R2 = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Lewis/diagnóstico por imagem , Carcinoma Pulmonar de Lewis/terapia , Doxorrubicina/análogos & derivados , Hipertermia Induzida , Imagem Óptica , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Lewis/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Feminino , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Temperatura Ambiente
19.
Urol Int ; 103(3): 285-290, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31461726

RESUMO

BACKGROUND: Topical therapy of nonmuscle-invasive bladder cancer (NMIBC) is based on immunotherapy with Bacillus Calmette-Guerin and chemotherapy administered by passive instillation, but an active drug administration achieves a better concentration of the drugs in the bladder. AIM: This study aimed to investigate the effectiveness of electromotive drug administration (EMDA) of mitomycin C (EMDA/MMC) in intermediate- and high-risk NMIBC patients 6 months after the end of induction treatment. MATERIALS AND METHODS: Sixty-five patients diagnosed with histologically confirmed NMIBC, with a complete transurethral resection of all visible tumors underwent EMDA/MMC. Primary endpoint was the proportion of responders at 3 or 6 months. RESULTS: Data on follow-up were available for 62 subjects at 3 months and 45 at 6 months. EMDA was effective in intermediate- and high-risk patients: because of the small number of cases no conclusions can be drawn on the efficacy in the low-risk group. No difference in the response to treatment between intermediate- (83.3%) and high-risk (84%) patients could be seen. CONCLUSIONS: EMDA/MMC is a useful technique for an effective and safe treatment of primary and recurrent NMIBC, and a valuable therapeutic option in intermediate- and high-risk NMIBC patients.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Eletroquimioterapia , Mitomicina/administração & dosagem , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/prevenção & controle , Administração Intravesical , Idoso , Feminino , Humanos , Masculino , Invasividade Neoplásica , Estudos Retrospectivos , Medição de Risco , Neoplasias da Bexiga Urinária/patologia
20.
Colloids Surf B Biointerfaces ; 181: 1012-1018, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31382328

RESUMO

Keratin is a good candidate for drug carrier due to its good biocompatibility, low immunogenicity, redox responsiveness, and abundant renewable sources. Herein, doxorubicin (DOX) was first conjugated with keratin through a pH-sensitive hydrazone linkage, and then prepared into particulate drug carrier via desolvation method. The size, morphology, and surface potential of keratin-DOX nanoparticles (KDNPs) were characterized by dynamic light scattering (DLS) and transmission electron microscopy (TEM). The drug release results showed that KDNPs performed an excellent pH-sensitive behavior under acidic tumor microenvironment. Cytotoxicity assay by MTT confirmed that KDNPs exhibited the enhanced cytotoxicity against A549 cells. Furthermore, KDNPs had higher therapeutic efficiency in vivo than free DOX. Hemolysis assay indicated that KDNPs was blood compatible. All the results identified that KDNPs are well suited as an ideal drug carrier.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Queratinas/química , Nanopartículas/química , Células A549 , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Concentração de Íons de Hidrogênio , Injeções Intravenosas , Cinética , Camundongos , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Tamanho da Partícula , Propriedades de Superfície
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