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1.
Int J Mol Sci ; 22(13)2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34208987

RESUMO

Pancreatic Cancer (PC) is recognized as a highly thrombogenic tumor; thus, low-molecular-weight heparin (LMWH) such as tinzaparin is routinely used for PC patients. On the basis of combinatorial therapy approaches to treat highly malignant and refractory cancers such as PC, we hypothesized that tinzaparin can augment the effectiveness of traditional chemotherapeutic drugs and induce efficient antitumor activity. PANC-1 and MIAPaCa-2 were incubated alone or in combination with tinzaparin, nab-paclitaxel and gemcitabine. In vivo evaluation of these compounds was performed in a NOD/SCID mouse using a model injected with PANC-1. Tinzaparin enhances the anti-tumor effects of nab-paclitaxel and gemcitabine in mtKRAS PC cell lines via apoptosis in in vitro experiments. The triple combination power acts through the induction of apoptosis, reduction of the proliferative potential and angiogenesis; hence, contributing to a decrease in tumor volume observed in vivo. The triple regimen provided an extra 24.3% tumor reduction compared to the double combination (gemcitabine plus nab-paclitaxel). Combinatorial strategies can create novel therapeutic approaches for the treatment of patients with PC, achieving a better clinical outcome and prolonged survival. Further prospective randomized research is needed and the investigation of various concentrations of tinzaparin above 150 UI/Kg, would potentially provide a valuable synergistic effect to the conventional therapeutic compounds.


Assuntos
Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/análogos & derivados , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Tinzaparina/administração & dosagem , Albuminas/farmacologia , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Paclitaxel/farmacologia , Neoplasias Pancreáticas/metabolismo , Tinzaparina/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
2.
Cochrane Database Syst Rev ; 6: CD009294, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34125951

RESUMO

BACKGROUND: It remains unclear whether people with non-muscle invasive bladder cancer (NMIBC) benefit from intravesical gemcitabine compared to other agents in the primary or recurrent setting following transurethral resection of a bladder tumor. This is an update of a Cochrane Review first published in 2012. Since that time, several randomized controlled trials (RCTs) have been reported, making this update relevant.  OBJECTIVES: To assess the comparative effectiveness and toxicity of intravesical gemcitabine instillation for NMIBC. SEARCH METHODS: We performed a comprehensive literature search of the Cochrane Library, MEDLINE, Embase, four other databases, trial registries, and conference proceedings to 11 September 2020, with no restrictions on the language or status of publication. SELECTION CRITERIA: We included RCTs in which participants received intravesical gemcitabine for primary or recurrent NMIBC. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: time to recurrence, time to progression, grade III to V adverse events determined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), and the secondary outcomes: time to death from bladder cancer, time to death from any cause, grade I or II adverse events determined by the CTCAE v5.0 and disease-specific quality of life. We performed statistical analyses using a random-effects model and rated the certainty of the evidence using GRADE. MAIN RESULTS: We included seven studies with 1222 participants with NMIBC across five comparisons. This abstract focuses on the primary outcomes of the three most clinically relevant comparisons. 1. Gemcitabine versus saline: based on two years' to four years' follow-up, gemcitabine may reduce the risk of recurrence over time compared to saline (39% versus 47% recurrence rate, hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.54 to 1.09; studies = 2, participants = 734; I2 = 49%; low-certainty evidence), but the CI included the possibility of no effect.  Gemcitabine may result in little to no difference in the risk of progression over time compared to saline (4.6% versus 4.8% progression rate, HR 0.96, 95% CI 0.19 to 4.71; studies = 2, participants = 654; I2 = 53%; low-certainty evidence).  Gemcitabine may result in little to no difference in the CTCAE grade III to V adverse events compared to saline (5.9% versus 4.7% adverse events rate, risk ratio [RR] 1.26, 95% CI 0.58 to 2.75; studies = 2, participants = 668; I2 = 24%; low-certainty evidence).  2. Gemcitabine versus mitomycin: based on three years' follow-up (studies = 1, participants = 109), gemcitabine may reduce the risk of recurrence over time compared to mitomycin (17% versus 40% recurrence rate, HR 0.36, 95% CI 0.19 to 0.69; low-certainty evidence). Gemcitabine may reduce the risk of progression over time compared to mitomycin (11% versus  18% progression rate, HR 0.57, 95% CI 0.32 to 1.01; low-certainty evidence), but the CI included the possibility of no effect.  We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to mitomycin (RR 0.51, 95% CI 0.13 to 1.93; very low-certainty evidence). The analysis was only based on recurrent NMIBC. 3. Gemcitabine versus Bacillus Calmette-Guérin (BCG) for recurrent (one-course BCG failure) high-risk NMIBC: based on 6 months' to 22 months' follow-up (studies = 1, participants = 80), gemcitabine may reduce the risk of recurrence compared to BCG (41% versus 97% recurrence rate, HR 0.15, 95% CI 0.09 to 0.26; low-certainty evidence) and progression over time (16% versus 33% progression rate, HR 0.45, 95% CI 0.27 to 0.76; low-certainty evidence). We are very uncertain about the effect of gemcitabine on the CTCAE grade III to V adverse events compared to BCG (RR 1.00, 95% CI 0.21 to 4.66; very low-certainty evidence).  In addition, the review provides information on  the comparison of gemcitabine versus BCG and gemcitabine versus one-third dose BCG.  AUTHORS' CONCLUSIONS: Based on findings of this review, gemcitabine may have a more favorable impact on recurrence and progression-free survival than mitomycin but we are very uncertain as to how major adverse events compare. The same is true when comparing gemcitabine to BCG in individuals with high risk disease who have previously failed BCG. The underlying low- to very low-certainty evidence indicates that our confidence in these results is limited; the true effects may be substantially different from these findings; therefore, better quality studies are needed.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Desoxicitidina/análogos & derivados , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias da Bexiga Urinária/tratamento farmacológico , Adjuvantes Imunológicos/administração & dosagem , Administração Intravesical , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/efeitos adversos , Vacina BCG/administração & dosagem , Viés , Causas de Morte , Intervalos de Confiança , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Progressão da Doença , Esquema de Medicação , Humanos , Mitomicina/administração & dosagem , Mitomicina/efeitos adversos , Recidiva Local de Neoplasia/mortalidade , Recidiva Local de Neoplasia/prevenção & controle , Ensaios Clínicos Controlados Aleatórios como Assunto , Solução Salina/administração & dosagem , Neoplasias da Bexiga Urinária/mortalidade , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/prevenção & controle
3.
Cancer Sci ; 112(6): 2335-2348, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33931930

RESUMO

Lysosomal degradation plays a crucial role in the metabolism of biological macromolecules supplied by autophagy. The regulation of the autophagy-lysosome system, which contributes to intracellular homeostasis, chemoresistance, and tumor progression, has recently been revealed as a promising therapeutic approach for pancreatic cancer (PC). However, the details of lysosomal catabolic function in PC cells have not been fully elucidated. In this study, we show evidence that suppression of acid alpha-glucosidase (GAA), one of the lysosomal enzymes, improves chemosensitivity and exerts apoptotic effects on PC cells through the disturbance of expression of the transcription factor EB. The levels of lysosomal enzyme were elevated by gemcitabine in PC cells. In particular, the levels of GAA were responsive to gemcitabine in a dose-dependent and time-dependent manner. Small interfering RNA against the GAA gene (siGAA) suppressed cell proliferation and promoted apoptosis in gemcitabine-treated PC cells. In untreated PC cells, we observed accumulation of depolarized mitochondria. Gene therapy using adenoviral vectors carrying shRNA against the GAA gene increased the number of apoptotic cells and decreased the tumor growth in xenograft model mice. These results indicate that GAA is one of the key targets to improve the efficacy of gemcitabine and develop novel therapies for PC.


Assuntos
Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos/genética , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , RNA Interferente Pequeno/administração & dosagem , alfa-Glucosidases/genética , Animais , Autofagia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Relação Dose-Resposta a Droga , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Lisossomos/efeitos dos fármacos , Lisossomos/enzimologia , Masculino , Camundongos , Camundongos Nus , Neoplasias Pancreáticas/enzimologia , Neoplasias Pancreáticas/genética , RNA Interferente Pequeno/farmacologia , Fatores de Tempo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Medicine (Baltimore) ; 100(21): e25980, 2021 May 28.
Artigo em Inglês | MEDLINE | ID: mdl-34032710

RESUMO

BACKGROUND: Concurrent chemoradiotherapy is widely utilised as a standardized primary method of treatment for patients with advanced nasopharyngeal carcinoma (NPC). However, the combination of concurrent chemoradiotherapy and adjuvant chemotherapy for treating NPC patients remain unclear. Therefore, this study attempts to elucidate the efficiency and safety of concurrent chemoradiotherapy combined with adjuvant chemotherapy (gemcitabine plus cisplatin versus 5-fluorouracil plus cisplatin) for treating patients with NPC. MATERIALS AND METHODS: This study is a randomized, multicentral, open-labelled trial to assess the clinical efficiency and safety of using concurrent chemoradiotherapy combined with adjuvant chemotherapy as a therapeutic measure for advanced NPC patients. A total of 50 patients will be randomly assigned into 2 groups, namely treatment-group-one and treatment-group-two. Eligible patients will be administered with concurrent chemoradiotherapy and subsequentially with adjuvant chemotherapy (gemcitabine plus cisplatin or 5-fluorouracil plus cisplatin). Moreover, the primary endpoint is a comparison of progression-free survival between concurrent chemoradiotherapy and subsequentially adjuvant gemcitabine and cisplatin and chemoradiotherapy, which is proceeded by adjuvant 5-fluorouracil and cisplatin in advanced NPC patients. Overall survival, overall response rate, incidence of acute and late toxicity, and adverse events are the minor endpoints. Statistical analyses will be performed with SPSS 25.0 software. DISCUSSION: The current research evaluates the clinical efficiency and safety of utilising concurrent chemoradiotherapy combined with adjuvant chemotherapy as a therapeutic strategy to treat advanced NPC patients. The work done in this study will provide a clinical basis for concurrent chemoradiotherapy in combination with adjuvant chemotherapy for treating advanced NPC. TRIAL REGISTRATION: DOI 10.17605/OSF.IO/5UPVM.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Quimiorradioterapia/métodos , Carcinoma Nasofaríngeo/terapia , Radioterapia de Intensidade Modulada/métodos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Quimiorradioterapia/efeitos adversos , Quimioterapia Adjuvante/efeitos adversos , Quimioterapia Adjuvante/métodos , Cisplatino/administração & dosagem , Cisplatino/efeitos adversos , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Esquema de Medicação , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Seguimentos , Humanos , Estudos Multicêntricos como Assunto , Carcinoma Nasofaríngeo/diagnóstico , Carcinoma Nasofaríngeo/mortalidade , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Radioterapia de Intensidade Modulada/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto
5.
Int J Mol Sci ; 22(9)2021 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-33946730

RESUMO

Granulosa cell tumors (GCT) constitute only ~5% of ovarian neoplasms yet have significant consequences, as up to 80% of women with recurrent GCT will die of the disease. This study investigated the effectiveness of procaspase-activating compound 1 (PAC-1), an activator of procaspase-3, in treating adult GCT (AGCT) in combination with selected apoptosis-inducing agents. Sensitivity of the AGCT cell line KGN to these drugs, alone or in combination with PAC-1, was tested using a viability assay. Our results show a wide range in cytotoxic activity among the agents tested. Synergy with PAC-1 was most pronounced, both empirically and by mathematical modelling, when combined with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). This combination showed rapid kinetics of apoptosis induction as determined by caspase-3 activity, and strongly synergistic killing of both KGN as well as patient samples of primary and recurrent AGCT. We have demonstrated that the novel combination of two pro-apoptotic agents, TRAIL and PAC-1, significantly amplified the induction of apoptosis in AGCT cells, warranting further investigation of this combination as a potential therapy for AGCT.


Assuntos
Tumor de Células da Granulosa/tratamento farmacológico , Hidrazonas/administração & dosagem , Neoplasias Ovarianas/tratamento farmacológico , Piperazinas/administração & dosagem , Ligante Indutor de Apoptose Relacionado a TNF/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/efeitos dos fármacos , Benzoquinonas/administração & dosagem , Carboplatina/administração & dosagem , Caspase 3/metabolismo , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Ativação Enzimática/efeitos dos fármacos , Feminino , Tumor de Células da Granulosa/enzimologia , Tumor de Células da Granulosa/patologia , Humanos , Técnicas In Vitro , Conceitos Matemáticos , Modelos Biológicos , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/patologia
6.
J Surg Oncol ; 123(6): 1395-1404, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33831247

RESUMO

The annual incidence of pancreatic cancer is nearly 50,000 patients. The 5-year overall survival is only 9%, and there remains a great need for better therapy. A subset of these patients presents with locally advanced disease. Multidisciplinary therapy has evolved to include some combination of systemic chemotherapy, locoregional radiation, and surgery in select patients with excellent biology. This review will address the thoughtful evidence-based and individualized approach to these patients.


Assuntos
Carcinoma Ductal Pancreático/terapia , Neoplasias Pancreáticas/terapia , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Quimiorradioterapia , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Gerenciamento Clínico , Medicina Baseada em Evidências , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Terapia Neoadjuvante , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Medicina de Precisão
7.
J Surg Oncol ; 123(6): 1432-1440, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33831253
8.
Cancer Treat Rev ; 96: 102180, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33812339

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive form of cancer with a dismal prognosis. The lack of symptoms in the early phase of the disease makes early diagnosis challenging, and about 80-85% of the patients are diagnosed only after the disease is locally advanced or metastatic. The current front-line treatment landscape in local stages comprises surgical resection and adjuvant chemotherapy. In Switzerland, although both FOLFIRINOX and gemcitabine plus nab-paclitaxel regimens are feasible and comparable in the first-line setting, FOLFIRINOX is preferred in the treatment of fit (Eastern Cooperative Oncology Group [ECOG] performance status [PS]: 0-1), young (<65 years old) patients with few comorbidities and normal liver function, while gemcitabine plus nab-paclitaxel is used to treat less fit (ECOG PS: 1-2) and more vulnerable patients. In the second-line setting of advanced PDAC, there is currently only one approved regimen, based on the phase III NAPOLI-1 trial. Furthermore, the use of liposomal-irinotecan in the second line is supported by real-world data. Beyond the standard of care, various alternative treatment modalities are being explored in clinical studies. Immunotherapy has demonstrated only limited benefits until now, and only in cases of high microsatellite instability (MSI-H). However, data on the benefit of poly (ADP-ribose) polymerase (PARP) inhibition as maintenance therapy in patients with germline BRCA-mutated tumors might signal of an advance in targeted therapy. Currently, there is a lack of molecular and genetic biomarkers for optimal stratification of patients and in guiding treatment decisions. Thus, identification of predictive and prognostic biomarkers and evaluating novel treatment strategies are equally relevant for improving the prognosis of metastatic pancreatic cancer patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Albuminas/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Carcinoma Ductal Pancreático/patologia , Carcinoma Ductal Pancreático/cirurgia , Ensaios Clínicos Fase III como Assunto , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Lipossomos/administração & dosagem , Metástase Neoplásica , Oxaliplatina/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Ensaios Clínicos Controlados Aleatórios como Assunto
9.
Am J Surg ; 221(6): 1182-1187, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33707077

RESUMO

BACKGROUND: The impact of neoadjuvant chemotherapy (NAC) on overall and recurrence-free survival (OS, RFS) in resectable intrahepatic cholangiocarcinoma (ICC) is poorly characterized. We sought to investigate the association of NAC with oncologic outcomes in ICC. METHODS: We identified n = 52 patients with ICC undergoing hepatectomy from 2004 to 2017. Oncologic outcomes were analyzed using Kaplan-Meier and multivariate Cox proportional hazard modeling. RESULTS: The median patient age was 64-years. NAC was administered in ten (19%) patients, most commonly with gemcitabine-cisplatin (n = 8, 80%). Median RFS and OS were 15 months. and 49 months, respectively. Controlling for stage and margins, NAC was independently associated with improved OS (HR 0.16, P = 0.01) but not RFS (HR 0.54, P = 0.27). NAC was not associated with major post-operative complications (P = 0.25) or R1 margins (P = 0.58). CONCLUSION: NAC in ICC may hold oncologic benefits beyond downstaging borderline resectable disease, such as identifying patients with favorable biology who are more likely to benefit from resection.


Assuntos
Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Hepatectomia , Terapia Neoadjuvante/métodos , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias dos Ductos Biliares/mortalidade , Neoplasias dos Ductos Biliares/cirurgia , Colangiocarcinoma/mortalidade , Colangiocarcinoma/cirurgia , Cisplatino/administração & dosagem , Cisplatino/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Feminino , Sobrevivência de Enxerto , Hepatectomia/métodos , Hepatectomia/mortalidade , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
10.
Int J Radiat Oncol Biol Phys ; 109(5): 1472-1482, 2021 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-33714528

RESUMO

PURPOSE: Chemoradiation therapy is the standard of care in muscle-invasive bladder cancer (MIBC). Although agents such as gemcitabine can enhance tumor radiosensitivity, their side effects can limit patient eligibility and treatment efficacy. This study investigates ultrasound and microbubbles for targeting gemcitabine delivery to reduce normal-tissue toxicity in a murine orthotopic MIBC model. MATERIALS AND METHODS: CD1-nude mice were injected orthotopically with RT112 bladder tumor cells. Conventional chemoradiation involved injecting gemcitabine (10 mg/kg) before 6 Gy targeted irradiation of the bladder area using the Small Animal Radiation Research Platform (SARRP). Ultrasound-mediated gemcitabine delivery (10 mg/kg gemcitabine) involved either coadministration of microbubbles with gemcitabine or conjugating gemcitabine onto microbubbles followed by exposure to ultrasound (1.1 MHz center frequency, 1 MPa peak negative pressure, 1% duty cycle, and 0.5 Hz pulse repetition frequency) before SARRP irradiation. The effect of ultrasound and microbubbles alone was also tested. Tumor volumes were measured by 3D ultrasound imaging. Acute normal-tissue toxicity from 12 Gy to the lower bowel area was assessed using an intestinal crypt assay in mice culled 3.75 days posttreatment. RESULTS: A significant delay in tumor growth was observed with conventional chemoradiation therapy and both microbubble groups (P < .05 compared with the radiation-only group). Transient weight loss was seen in the microbubble groups, which resolved within 10 days posttreatment. A positive correlation was found between weight loss on day 3 posttreatment and tumor growth delay (P < .05; R2 = 0.76). In contrast with conventional chemoradiation therapy, ultrasound-mediated drug delivery methods did not exacerbate the acute intestinal toxicity using the crypt assay. CONCLUSIONS: Ultrasound and microbubbles offer a promising new approach for improving chemoradiation therapy for muscle-invasive bladder cancer, maintaining a delay in tumor growth but with reduced acute intestinal toxicity compared with conventional chemoradiation therapy.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Quimiorradioterapia/efeitos adversos , Desoxicitidina/análogos & derivados , Órgãos em Risco/efeitos da radiação , Lesões por Radiação/prevenção & controle , Neoplasias da Bexiga Urinária/terapia , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Biotinilação , Linhagem Celular Tumoral , Quimiorradioterapia/métodos , Meios de Contraste/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/síntese química , Feminino , Humanos , Intestinos/efeitos da radiação , Camundongos , Camundongos Nus , Microbolhas , Invasividade Neoplásica , Carga Tumoral , Ultrassonografia , Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/diagnóstico por imagem , Neoplasias da Bexiga Urinária/patologia
11.
ACS Appl Mater Interfaces ; 13(11): 12824-12835, 2021 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-33689289

RESUMO

Pancreatic tumor is extremely lethal because its cancerous structures are sheltered by dense stromal barriers that hinder the infiltration of therapeutics. To facilitate the infiltration of therapeutics through the stromal barrier, remodeling the stroma with an adjuvant prior to or together with gemcitabine-the current chemotherapeutic standard for pancreatic cancer-is a widely studied strategy; nevertheless, the intrinsic nonuniformity in distribution (spatial and/or temporal) of the adjuvant and gemcitabine has raised the increased risk of tumor metastasis as a major concern. In this work, we propose long-circulating, pH-sensitive nanoparticles composed solely of cellular membrane-disruptive molecules as a new approach for treating pancreatic cancer. Using a micelle of a polymeric mimetic of host defense peptides as the model for such nanoparticles, we showed that this nanoparticle exhibited acid-activated cytotoxicity indiscriminately to both cancerous and fibroblast cells, and the underlying activity mode was acid-activatable disruption of cellular membrane integrity. As a result, our acid-activatable nanoparticle effectively permeabilized the stromal barrier and eradicated the otherwise sheltered pancreatic cancer cells, as demonstrated with a three-dimensional spheroid in which a shell of fibroblast NIH-3T3 cells was cultured over a core of pancreatic BxPC-3 cells. When administered intravenously into mouse models bearing xenograft pancreatic BxPC-3 tumors, our acid-activatable nanoparticle efficiently inhibited tumor growth without causing noticeable off-target adverse effects or promoting tumor metastasis. Notably, this nanoparticle permeabilized the otherwise dense pancreatic tumor tissue while significantly suppressing the expression of extracellular matrix components and activated cancer-associated fibroblasts. Although the feasibility of our approach was demonstrated with a micelle of a polymeric molecule, we trust that future research efforts in this pathway may eventually offer translational formulations for improving the therapeutic efficacy of pancreatic cancer.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Desoxicitidina/análogos & derivados , Nanopartículas/química , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Células NIH 3T3
12.
Ultrasound Med Biol ; 47(6): 1596-1615, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33707089

RESUMO

In this study we compared three different microbubble-based approaches to the delivery of a widely used chemotherapy drug, gemcitabine: (i) co-administration of gemcitabine and microbubbles (Gem+MB); (ii) conjugates of microbubbles and gemcitabine-loaded liposomes (GemlipoMB); and (iii) microbubbles with gemcitabine directly bound to their surfaces (GembioMB). Both in vitro and in vivo investigations were carried out, respectively, in the RT112 bladder cancer cell line and in a murine orthotopic muscle-invasive bladder cancer model. The in vitro (in vivo) ultrasound exposure conditions were a 1 (1.1) MHz centre frequency, 0.07 (1.0) MPa peak negative pressure, 3000 (20,000) cycles and 100 (0.5) Hz pulse repetition frequency. Ultrasound exposure produced no significant increase in drug uptake either in vitro or in vivo compared with the drug-only control for co-administered gemcitabine and microbubbles. In vivo, GemlipoMB prolonged the plasma circulation time of gemcitabine, but only GembioMB produced a statistically significant increase in cleaved caspase 3 expression in the tumor, indicative of gemcitabine-induced apoptosis.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Antimetabólitos Antineoplásicos/farmacocinética , Desoxicitidina/análogos & derivados , Sistemas de Liberação de Medicamentos/métodos , Microbolhas , Terapia por Ultrassom , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/terapia , Animais , Antimetabólitos Antineoplásicos/uso terapêutico , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacocinética , Desoxicitidina/uso terapêutico , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Nus , Células Tumorais Cultivadas
13.
Oncology ; 99(6): 365-372, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33730723

RESUMO

BACKGROUND: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. PATIENTS AND METHODS: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score positivity. RESULTS: Of the 186 patients, the primary tumor location was intrahepatic cholangiocarcinoma (IHCC) in 72 (38.7%), extrahepatic cholangiocarcinoma (EHCC) in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). Among all the patients, 53 (28.5%) had PD-L1 positivity. The median overall survival (OS) of patients with PD-L1 positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. OS and PFS were not statistically different between groups. In subgroup analysis, EHCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p = 0.002) and PFS (7.8 vs. 5.4 months, p = 0.005) than those who were PD-L1-positive. However, this finding was not reproduced in patients with IHCC or GB cancer. CONCLUSION: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EHCC but not in patients with IHCC or GB cancer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Antígeno B7-H1/metabolismo , Neoplasias dos Ductos Biliares/tratamento farmacológico , Biomarcadores Tumorais/metabolismo , Colangiocarcinoma/tratamento farmacológico , Desoxicitidina/análogos & derivados , Neoplasias da Vesícula Biliar/tratamento farmacológico , Platina/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/metabolismo , Colangiocarcinoma/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Feminino , Neoplasias da Vesícula Biliar/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Paliativos , Platina/uso terapêutico , Prognóstico , Análise de Sobrevida , Resultado do Tratamento
14.
BMC Cancer ; 21(1): 300, 2021 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-33757440

RESUMO

BACKGROUND: Neoadjuvant therapy has several potential advantages over upfront surgery in patients with localized pancreatic cancer; more patients receive systemic treatment, fewer patients undergo futile surgery, and R0 resection rates are higher, thereby possibly improving overall survival (OS). Two recent randomized trials have suggested benefit of neoadjuvant chemoradiotherapy over upfront surgery, both including single-agent chemotherapy regimens. Potentially, the multi-agent FOLFIRINOX regimen (5-fluorouracil with leucovorin, irinotecan, and oxaliplatin) may further improve outcomes in the neoadjuvant setting for localized pancreatic cancer, but randomized studies are needed. The PREOPANC-2 trial investigates whether neoadjuvant FOLFIRINOX improves OS compared with neoadjuvant gemcitabine-based chemoradiotherapy and adjuvant gemcitabine in resectable and borderline resectable pancreatic cancer patients. METHODS: This nationwide multicenter phase III randomized controlled trial includes patients with pathologically confirmed resectable and borderline resectable pancreatic cancer with a WHO performance score of 0 or 1. Resectable pancreatic cancer is defined as no arterial and ≤ 90 degrees venous involvement; borderline resectable pancreatic cancer is defined as ≤90 degrees arterial and ≤ 270 degrees venous involvement without occlusion. Patients receive 8 cycles of neoadjuvant FOLFIRINOX chemotherapy followed by surgery without adjuvant treatment (arm A), or 3 cycles of neoadjuvant gemcitabine with hypofractionated radiotherapy (36 Gy in 15 fractions) during the second cycle, followed by surgery and 4 cycles of adjuvant gemcitabine (arm B). The primary endpoint is OS by intention-to-treat. Secondary endpoints include progression-free survival, quality of life, resection rate, and R0 resection rate. To detect a hazard ratio of 0.70 with 80% power, 252 events are needed. The number of events is expected to be reached after inclusion of 368 eligible patients assuming an accrual period of 3 years and 1.5 years follow-up. DISCUSSION: The PREOPANC-2 trial directly compares two neoadjuvant regimens for patients with resectable and borderline resectable pancreatic cancer. Our study will provide evidence on the neoadjuvant treatment of choice for patients with resectable and borderline resectable pancreatic cancer. TRIAL REGISTRATION: Primary registry and trial identifying number: EudraCT: 2017-002036-17 . Date of registration: March 6, 2018. Secondary identifying numbers: The Netherlands National Trial Register - NL7094 , NL61961.078.17, MEC-2018-004.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Quimiorradioterapia/métodos , Neoplasias Pancreáticas/terapia , Ensaios Clínicos Controlados Aleatórios como Assunto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Fluoruracila/administração & dosagem , Humanos , Irinotecano/administração & dosagem , Leucovorina/administração & dosagem , Terapia Neoadjuvante , Oxaliplatina/administração & dosagem , Neoplasias Pancreáticas/mortalidade
15.
Oncology ; 99(5): 300-309, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33657549

RESUMO

BACKGROUND: Unresectable cholangiocarcinoma has a poor prognosis and treatment options are limited. Combined systemic and intrahepatic chemotherapy may improve local control and enable downsizing. The aim of this study was to determine the maximum tolerated dose (MTD) of intravenous gemcitabine combined with intravenous cisplatin and hepatic arterial infusion (HAI) with floxuridine (FUDR) in patients with unresectable intrahepatic or hilar cholangiocarcinoma. METHODS: Twelve patients were treated within a 3 + 3 dose escalation algorithm with 600, 800, or 1,000 mg/m2 gemcitabine and predefined doses of cisplatin 25 mg/m2 on days 1 and 8, q21, for 4 cycles, and FUDR 0.2 mg/kg on days 1-14 as continuous HAI, q28, for 3 cycles. Safety and toxicity as well as resectability rates after 3 months and preliminary survival data are reported. RESULTS: The determined MTD for gemcitabine was 800 mg/m2. Dose limiting toxicities were neutropenic fever and biliary tract infections. In total, 27% of the patients showed partial remission and 73% stable disease. Although none of the patients achieved resectability after 3 months, the 3-year overall survival rate was 33%, median overall survival 23.9 months (range 1-49), and median progression-free survival 10.1 months (range 2-40). CONCLUSIONS: Intravenous gemcitabine/cisplatin plus HAI-FUDR is feasible and appears effective for disease control. Larger prospective studies evaluating this triplet combination are warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Colangiocarcinoma/tratamento farmacológico , Artéria Hepática , Adulto , Idoso , Neoplasias dos Ductos Biliares/patologia , Colangiocarcinoma/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Floxuridina/administração & dosagem , Seguimentos , Humanos , Infusões Intra-Arteriais , Masculino , Pessoa de Meia-Idade , Ensaios Clínicos Controlados não Aleatórios como Assunto , Prognóstico , Estudos Prospectivos , Taxa de Sobrevida
16.
Gastroenterology ; 160(6): 2119-2132.e9, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33524400

RESUMO

BACKGROUND AND AIMS: Homologous recombination deficiency (HRD) in pancreatic ductal adenocarcinoma (PDAC), remains poorly defined beyond germline (g) alterations in BRCA1, BRCA2, and PALB2. METHODS: We interrogated whole genome sequencing (WGS) data on 391 patients, including 49 carriers of pathogenic variants (PVs) in gBRCA and PALB2. HRD classifiers were applied to the dataset and included (1) the genomic instability score (GIS) used by Myriad's MyChoice HRD assay; (2) substitution base signature 3 (SBS3); (3) HRDetect; and (4) structural variant (SV) burden. Clinical outcomes and responses to chemotherapy were correlated with HRD status. RESULTS: Biallelic tumor inactivation of gBRCA or PALB2 was evident in 43 of 49 germline carriers identifying HRD-PDAC. HRDetect (score ≥0.7) predicted gBRCA1/PALB2 deficiency with highest sensitivity (98%) and specificity (100%). HRD genomic tumor classifiers suggested that 7% to 10% of PDACs that do not harbor gBRCA/PALB2 have features of HRD. Of the somatic HRDetecthi cases, 69% were attributed to alterations in BRCA1/2, PALB2, RAD51C/D, and XRCC2, and a tandem duplicator phenotype. TP53 loss was more common in BRCA1- compared with BRCA2-associated HRD-PDAC. HRD status was not prognostic in resected PDAC; however in advanced disease the GIS (P = .02), SBS3 (P = .03), and HRDetect score (P = .005) were predictive of platinum response and superior survival. PVs in gATM (n = 6) or gCHEK2 (n = 2) did not result in HRD-PDAC by any of the classifiers. In 4 patients, BRCA2 reversion mutations associated with platinum resistance. CONCLUSIONS: Germline and parallel somatic profiling of PDAC outperforms germline testing alone in identifying HRD-PDAC. An additional 7% to 10% of patients without gBRCA/PALB2 mutations may benefit from DNA damage response agents.


Assuntos
Carcinoma Ductal Pancreático/genética , Proteína do Grupo de Complementação N da Anemia de Fanconi/genética , Genes BRCA1 , Genes BRCA2 , Neoplasias Pancreáticas/genética , Reparo de DNA por Recombinação , Idoso , Alelos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Cisplatino/administração & dosagem , Proteínas de Ligação a DNA/genética , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Fluoruracila/uso terapêutico , Instabilidade Genômica , Mutação em Linhagem Germinativa , Recombinação Homóloga , Humanos , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Oxaliplatina/uso terapêutico , Pancreatectomia , Neoplasias Pancreáticas/terapia , Prognóstico , Sensibilidade e Especificidade , Taxa de Sobrevida , Proteína Supressora de Tumor p53/genética , Sequenciamento Completo do Genoma
17.
Ann Hematol ; 100(7): 1755-1767, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33625572

RESUMO

The optimal salvage therapy in relapsed/refractory Hodgkin lymphoma (R/R HL) has not been defined so far. The goal of this multicenter retrospective study was to evaluate efficacy and safety of BGD (bendamustine, gemcitabine, dexamethasone) as a second or subsequent line of therapy in classical R/R HL. We have evaluated 92 consecutive R/R HL patients treated with BGD. Median age was 34.5 (19-82) years. Fifty-eight patients (63%) had received 2 or more lines of chemotherapy, 32 patients (34.8%) radiotherapy, and 21 patients (22.8%) an autologous hematopoietic stem cell transplantation (autoHCT). Forty-four patients (47.8%) were resistant to first line of chemotherapy. BGD therapy consisted of bendamustine 90 mg/m2 on days 1 and 2, gemcitabine 800 mg/m2 on days 1 and 4, dexamethasone 40 mg on days 1-4. Median number of BGD cycles was 4 (2-7). The following adverse events ≥ 3 grade were noted: neutropenia (22.8%), thrombocytopenia (20.7%), anemia (15.2%), infections (10.9%), AST/ALT increase (2.2%), and skin rush (1.1%). After BGD therapy, 51 (55.4%) patients achieved complete remission, 23 (25%)-partial response, 7 (7.6%)-stable disease, and 11 (12%) patients experienced progression disease. AutoHCT was conducted in 42 (45.7%) patients after BGD therapy, and allogeneic HCT (alloHCT) in 16 (17.4%) patients. Median progression-free survival was 21 months. BGD is a highly effective, well-tolerated salvage regimen for patients with R/R HL, providing an excellent bridge to auto- or alloHCT.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Terapia de Salvação , Adulto , Idoso , Idoso de 80 Anos ou mais , Aloenxertos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Cloridrato de Bendamustina/administração & dosagem , Cloridrato de Bendamustina/efeitos adversos , Terapia Combinada , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Dexametasona/administração & dosagem , Dexametasona/efeitos adversos , Avaliação de Medicamentos , Feminino , Doenças Hematológicas/induzido quimicamente , Transplante de Células-Tronco Hematopoéticas , Doença de Hodgkin/radioterapia , Doença de Hodgkin/terapia , Humanos , Infecções/etiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Radioterapia Adjuvante , Recidiva , Estudos Retrospectivos , Transplante Autólogo , Adulto Jovem
18.
BMC Cancer ; 21(1): 200, 2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33637083

RESUMO

BACKGROUND: Mesothelin is a 40-kDa glycoprotein that is highly overexpressed in various types of cancers, however molecular mechanism of mesothelin has not been well-known. Amatuximab is a chimeric monoclonal IgG1/k antibody targeting mesothelin. We recently demonstrated that the combine therapy of Amatuximab and gemcitabine was effective for peritonitis of pancreatic cancer in mouse model. METHODS: We discover the role and potential mechanism of mesothelin blockage by Amatuximab in human pancreatic cells both expressing high or low level of mesothelin in vitro experiment and peritonitis mouse model of pancreatic cancer. RESULTS: Mesothelin blockage by Amatuximab lead to suppression of invasiveness and migration capacity in AsPC-1 and Capan-2 (high mesothelin expression) and reduce levels of pMET expression. The combination of Amatuximab and gemcitabine suppressed proliferation of AsPC-1 and Capan-2 more strongly than gemcitabine alone. These phenomena were not observed in Panc-1 and MIA Paca-2 (Mesothelin low expression). We previously demonstrated that Amatuximab reduced the peritoneal mass in mouse AsPC-1 peritonitis model and induced sherbet-like cancer cell aggregates, which were vanished by gemcitabine. In this study, we showed that the cancer stem cell related molecule such as ALDH1, CD44, c-MET, as well as proliferation related molecules, were suppressed in sherbet-like aggregates, but once sherbet-like aggregates attached to peritoneum, they expressed these molecules strongly without the morphological changes. CONCLUSIONS: Our work suggested that Amatuximab inhibits the adhesion of cancer cells to peritoneum and suppresses the stemness and viability of those, that lead to enhance the sensitivity for gemcitabine.


Assuntos
Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/tratamento farmacológico , Desoxicitidina/análogos & derivados , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas de Neoplasias/antagonistas & inibidores , Células-Tronco Neoplásicas/efeitos dos fármacos , Neoplasias Pancreáticas/tratamento farmacológico , Animais , Anticorpos Monoclonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/prevenção & controle , Carcinoma Ductal Pancreático/secundário , Adesão Celular/efeitos dos fármacos , Agregação Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Sinergismo Farmacológico , Feminino , Proteínas Ligadas por GPI/biossíntese , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/imunologia , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Invasividade Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Células-Tronco Neoplásicas/patologia , Tamanho do Órgão/efeitos dos fármacos , Neoplasias Pancreáticas/patologia , Neoplasias Peritoneais/prevenção & controle , Neoplasias Peritoneais/secundário , Peritônio/efeitos dos fármacos , Peritônio/metabolismo , Peritônio/patologia , Peritonite/tratamento farmacológico , Peritonite/patologia
19.
Lancet ; 397(10274): 592-604, 2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33581821

RESUMO

BACKGROUND: We aimed to examine cemiplimab, a programmed cell death 1 inhibitor, in the first-line treatment of advanced non-small-cell lung cancer with programmed cell death ligand 1 (PD-L1) of at least 50%. METHODS: In EMPOWER-Lung 1, a multicentre, open-label, global, phase 3 study, eligible patients recruited in 138 clinics from 24 countries (aged ≥18 years with histologically or cytologically confirmed advanced non-small-cell lung cancer, an Eastern Cooperative Oncology Group performance status of 0-1; never-smokers were ineligible) were randomly assigned (1:1) to cemiplimab 350 mg every 3 weeks or platinum-doublet chemotherapy. Crossover from chemotherapy to cemiplimab was allowed following disease progression. Primary endpoints were overall survival and progression-free survival per masked independent review committee. Primary endpoints were assessed in the intention-to-treat population and in a prespecified PD-L1 of at least 50% population (per US Food and Drug Administration request to the sponsor), which consisted of patients with PD-L1 of at least 50% per 22C3 assay done according to instructions for use. Adverse events were assessed in all patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT03088540 and is ongoing. FINDINGS: Between June 27, 2017 and Feb 27, 2020, 710 patients were randomly assigned (intention-to-treat population). In the PD-L1 of at least 50% population, which consisted of 563 patients, median overall survival was not reached (95% CI 17·9-not evaluable) with cemiplimab (n=283) versus 14·2 months (11·2-17·5) with chemotherapy (n=280; hazard ratio [HR] 0·57 [0·42-0·77]; p=0·0002). Median progression-free survival was 8·2 months (6·1-8·8) with cemiplimab versus 5·7 months (4·5-6·2) with chemotherapy (HR 0·54 [0·43-0·68]; p<0·0001). Significant improvements in overall survival and progression-free survival were also observed with cemiplimab in the intention-to-treat population despite a high crossover rate (74%). Grade 3-4 treatment-emergent adverse events occurred in 98 (28%) of 355 patients treated with cemiplimab and 135 (39%) of 342 patients treated with chemotherapy. INTERPRETATION: Cemiplimab monotherapy significantly improved overall survival and progression-free survival compared with chemotherapy in patients with advanced non-small-cell lung cancer with PD-L1 of at least 50%, providing a potential new treatment option for this patient population. FUNDING: Regeneron Pharmaceuticals and Sanofi.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antígeno B7-H1/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Idoso , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carboplatina/administração & dosagem , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Cisplatino/administração & dosagem , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Humanos , Neoplasias Pulmonares/metabolismo , Masculino , Pessoa de Meia-Idade , Paclitaxel/administração & dosagem , Pemetrexede/administração & dosagem , Intervalo Livre de Progressão , Taxa de Sobrevida
20.
Int J Nanomedicine ; 16: 683-700, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33536754

RESUMO

Purpose: To develop an externally triggered rapid-release targeted system for treating ovarian cancer, gemcitabine (GMC) was entrapped into sonosensitive (SoS) folate (Fo)-modified liposomes (LPs). Methods: GMC-loaded LPs (GMC LPs), GMC-loaded Fo-targeted LPs (GMC-Fo LPs), and GMC-loaded Fo-targeted SoS LPs (GMC-SoS Fo LPs) were prepared utilizing a film-hydration technique and evaluated based on particle size, ζ-potential, and percentage entrapped drug. Cellular uptake of the fluorescent delivery systems in Fo-expressing ovarian cancer cells was quantified using flow cytometry. Finally, tumor-targeting ability, in vivo evaluation, and pharmacokinetic studies were performed. Results: GMC LPs, GMC-Fo LPs, and GMC-SoS Fo LPs were successfully prepared, with sizes of <120.3±2.4 nm, 39.7 mV ζ-potential, and 86.3%±1.84% entrapped drug. Cellular uptake of GMC-SoS Fo LPs improved 6.51-fold over GMC LPs (under ultrasonic irradiation - p<0.05). However, cellular uptake of GMC-Fo LPs improved just 1.24-fold over GMC LPs (p>0.05). Biodistribution study showed that of GMC concentration in tumors treated with GMC-SoS-Fo LPs (with ultrasound) improved 2.89-fold that of free GMC (p<0.05). In vivo, GMC-SoS Fo LPs showed the highest antiproliferative and antitumor action on ovarian cancer. Conclusion: These findings showed that externally triggered rapid-release SoS Fo-modified LPs are a promising system for delivering rapid-release drugs into tumors.


Assuntos
Desoxicitidina/análogos & derivados , Ácido Fólico/química , Ultrassom , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/sangue , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Desoxicitidina/administração & dosagem , Desoxicitidina/sangue , Desoxicitidina/farmacocinética , Desoxicitidina/farmacologia , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Endocitose/efeitos dos fármacos , Feminino , Humanos , Lipossomos , Neoplasias Ovarianas/sangue , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Tamanho da Partícula , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos
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