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1.
Anticancer Res ; 41(9): 4505-4513, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475076

RESUMO

BACKGROUND: The tumor vascular microenvironment has an important role in tumor progression and metastasis. The objective of this study was to assess the significance of metastatic hepatic tumor vascular microenvironment in relation to the response to systemic fluorouracil-based chemotherapy [folinic acid/fluorouracil/oxaliplatin (FOLFOX) or folinic acid/fluorouracil/irinotecan (FOLFIRI)]. PATIENTS AND METHODS: A total of 48 consecutive patients with colorectal cancer (CRC) with hepatic metastasis were retrospectively reviewed, and factors such as metastatic tumor vascular microenvironment, chemotherapy response and hepatic resection, were analyzed. Tumor angiogenesis was microscopically evaluated by microvessel density (MVD) in sections stained immunochemically with antibody to CD34 in patients with hepatic resection. Angiogenesis in the tumor microenvironment in association with ring enhancement (RE) on computed tomography (CT) was also examined. RESULTS: Microscopic examination revealed that peripheral RE on CT of the metastatic tumor was associated with tumor angiogenesis by MVD. The overall response rate after six courses of first-line chemotherapy for liver metastasis with RE on CT was 64% (23/36), whereas the response rate for those without RE was 25% (3/12), which was significantly lower, although the survival of patients with RE-positive and RE-negative tumors did not differ significantly. CONCLUSION: Peripheral RE of metastatic hepatic tumor on CT was associated with angiogenesis in the tumor microenvironment and higher chemotherapy response.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD34/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Camptotecina/análogos & derivados , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Colorretais/metabolismo , Angiografia por Tomografia Computadorizada , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/metabolismo , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Estudos Retrospectivos , Análise de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos
2.
Nat Commun ; 12(1): 3362, 2021 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-34099692

RESUMO

Diabetes can be caused by an insufficiency in ß-cell mass. Here, we performed a genetic screen in a zebrafish model of ß-cell loss to identify pathways promoting ß-cell regeneration. We found that both folate receptor 1 (folr1) overexpression and treatment with folinic acid, stimulated ß-cell differentiation in zebrafish. Treatment with folinic acid also stimulated ß-cell differentiation in cultures of neonatal pig islets, showing that the effect could be translated to a mammalian system. In both zebrafish and neonatal pig islets, the increased ß-cell differentiation originated from ductal cells. Mechanistically, comparative metabolomic analysis of zebrafish with/without ß-cell ablation and with/without folinic acid treatment indicated ß-cell regeneration could be attributed to changes in the pyrimidine, carnitine, and serine pathways. Overall, our results suggest evolutionarily conserved and previously unknown roles for folic acid and one-carbon metabolism in the generation of ß-cells.


Assuntos
Carbono/metabolismo , Diferenciação Celular/efeitos dos fármacos , Receptor 1 de Folato/metabolismo , Células Secretoras de Insulina/metabolismo , Leucovorina/farmacologia , Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Animais Recém-Nascidos , Carnitina/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Receptor 1 de Folato/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Células Secretoras de Insulina/citologia , Larva/genética , Larva/metabolismo , Redes e Vias Metabólicas/efeitos dos fármacos , Camundongos , Pirimidinas/metabolismo , Suínos , Peixe-Zebra/genética
3.
Int J Mol Sci ; 22(3)2021 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-33572934

RESUMO

(1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer studies with gas chromatography/mass spectrometry (GC/MS) platforms, we systematically investigated how MTX interferes with the partitioning of mitochondrial and cytosolic formate metabolism. (3) Results: MTX significantly reduced de novo deoxythymidylate (dTMP) and methionine biosyntheses from mitochondrial-derived formate in cells, mouse liver, and bone marrow, supporting our postulation that MTX depletes mitochondrial 1C supply. Furthermore, MTX inhibited formate generation from mitochondria glycine cleavage system (GCS) both in vitro and in vivo. Folinate selectively rescued 1C metabolic pathways in a tissue-, cellular compartment-, and pathway-specific manner: folinate effectively reversed the inhibition of mitochondrial formate-dependent 1C metabolism in mouse bone marrow (dTMP, methionine, and GCS) and cells (dTMP and GCS) but not methionine synthesis in liver/liver-derived cells. Folinate failed to fully recover hepatic mitochondrial-formate utilization for methionine synthesis, suggesting that the efficacy of clinical folinate rescue in MTX therapy on hepatic methionine metabolism is poor. (4) Conclusion: Conducting studies in mouse and cell models, we demonstrate novel findings that MTX specifically depletes mitochondrial 1C supply that can be ameliorated by folinate supplementation except for hepatic transmethylation. These results imply that clinical use of low-dose MTX may particularly impede 1C metabolism via depletion of mitochondrial formate. The MTX induced systematic and tissue-specific formate depletion needs to be addressed more carefully, and the efficacy of folinate with respect to protecting against such depletion deserves to be evaluated in medical practice.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Formiatos/metabolismo , Leucovorina/uso terapêutico , Metotrexato/uso terapêutico , Complexo Vitamínico B/uso terapêutico , Animais , Antirreumáticos/farmacologia , Artrite Reumatoide/metabolismo , Suplementos Nutricionais , Feminino , Humanos , Leucovorina/farmacologia , Redes e Vias Metabólicas/efeitos dos fármacos , Metotrexato/farmacologia , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Complexo Vitamínico B/farmacologia
4.
Mol Cancer ; 20(1): 10, 2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33407548

RESUMO

BACKGROUND: FOLFOX is a combinational regimen of folinic acid (FnA, FOL), fluorouracil (5-Fu, F) and oxaliplatin (OxP, OX), and has been long considered as the standard treatment of colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Recent developments of nano delivery systems have provided profound promise for improving anticancer efficacy and alleviating side effects of FOLFOX. Previously, a nanoformulation (termed Nano-Folox) containing OxP derivative and FnA was developed in our laboratory using nanoprecipitation technique. Nano-Folox induced OxP-mediated immunogenic cell death (ICD)-associated antitumor immunity, which significantly suppressed tumor growth in the orthotopic CRC mouse model when administrated in combination with free 5-Fu. METHODS: A nanoformulation (termed Nano-FdUMP) containing FdUMP (5-Fu active metabolite) was newly developed using nanoprecipitation technique and used in combination with Nano-Folox for CRC and HCC therapies. RESULTS: Synergistic efficacy was achieved in orthotopic CRC and HCC mouse models. It resulted mainly from the fact that Nano-FdUMP mediated the formation of reactive oxygen species (ROS), which promoted the efficacy of ICD elicited by Nano-Folox. In addition, combination of Nano-Folox/Nano-FdUMP and anti-PD-L1 antibody significantly inhibited CRC liver metastasis, leading to long-term survival in mice. CONCLUSION: This study provides proof of concept that combination of two nano delivery systems can result in successful FOLFOX-associated CRC and HCC therapies. Further optimization in terms of dosing and timing will enhance clinical potential of this combination strategy for patients.


Assuntos
Carcinoma Hepatocelular/tratamento farmacológico , Carcinoma Hepatocelular/imunologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/imunologia , Morte Celular Imunogênica , Neoplasias Hepáticas/tratamento farmacológico , Nanopartículas/química , Espécies Reativas de Oxigênio/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Modelos Animais de Doenças , Composição de Medicamentos , Sinergismo Farmacológico , Feminino , Fluordesoxiuridilato/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Morte Celular Imunogênica/efeitos dos fármacos , Imunoterapia , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Nanopartículas/ultraestrutura , Metástase Neoplásica , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Distribuição Tecidual
5.
PLoS One ; 16(1): e0245581, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33465114

RESUMO

Evasion of apoptosis is associated with treatment resistance and metastasis in colorectal cancer (CRC). Various cellular processes are associated with evasion of apoptosis. These include overexpression of pro-apoptotic proteins (including p53 and PD-L1), anti-apoptotic proteins (BIRC7/Livin and Bcl-2), chemokine receptors (including DARC), and dysregulation of DNA mismatch repair proteins (including MSH2 and PMS2). The aim of this study was to determine the effect of folinic acid, 5-FU and oxaliplatin (FOLFOX) as a single agent and aspirin plus FOLFOX in various combinations on the aforementioned proteins in human CRC, SW480 cell line and rat models of N-Methyl-N-Nitrosourea (NMU)-induced CRC. In addition, effects of the NMU-induced CRC and chemotherapeutic regimens on haematological and biochemical parameters in the rat models were studied. Immunohistochemistry, immunofluorescence and immunoblot techniques were used to study the expression pattern of the related proteins in the human CRC cells pre- and post-treatment. Double contrast barium enema, post-mortem examination and histological analyses were used to confirm tumour growth and the effect of the treatment in vivo in rat models. Notably, we found in human mucinous CRC, a significant increase in expression of the BIRC7/Livin post-FOLFOX treatment compared with pre-treatment (p = 0.0001). This increase provides new insights into the prognostic role of BIRC7/Livin in evasion of apoptosis and facilitation of treatment resistance, local recurrence and metastasis particularly among mucinous CRCs post-FOLFOX chemotherapy. These poor prognostic features in the CRC may be further compounded by the significant suppression of DARC, PD-L1, PMS2 and overexpression of MSH2 and anti-apoptotic Bcl-2 and p53 proteins observed in our study (p < 0.05). Importantly, we found a significant reduction in expression of BIRC7/Livin and reactivation of DARC and PD-L1 with a surge in Annexin V expression in rat models of CRC cells post-treatment with a sequential dose of aspirin plus FOLFOX compared with other treatments in vivo (p <0.05). The mechanistic rational of these effects underscores the importance of expanded concept of possible aspirin combination therapy with FOLFOX sequentially in future CRC management. Validation of our findings through randomized clinical trials of aspirin plus FOLFOX sequentially in patients with CRC is therefore warranted.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Aspirina/farmacologia , Biomarcadores Tumorais/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Anexina A5/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Apoptose/efeitos dos fármacos , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/patologia , Reparo de Erro de Pareamento de DNA/efeitos dos fármacos , Interações Medicamentosas , Sistema do Grupo Sanguíneo Duffy/metabolismo , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Proteínas Inibidoras de Apoptose/metabolismo , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Masculino , Endonuclease PMS2 de Reparo de Erro de Pareamento/metabolismo , Proteína 2 Homóloga a MutS/metabolismo , Proteínas de Neoplasias/metabolismo , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Prognóstico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Receptores de Superfície Celular/metabolismo , Proteína Supressora de Tumor p53/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto
6.
Cancer Invest ; 39(1): 62-72, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33258714

RESUMO

To dissect gene expression subgroups of FOLFOX resistance colorectal cancer(CRC) and predict FOLFOX response, gene expression data of 83 stage IV CRC tumor samples (FOLFOX responder n = 42, non-responder n = 41) are used to develop a novel iterative supervised learning method IML. IML identified two mutually exclusive subgroups of CRC patients that rely on different DNA damage repair proteins and resist FOLFOX. IML was validated in two validation sets (HR = 2.6, p Value = 0.02; HR = 2.36, p value = 0.02). A subgroup of mesenchymal subtype patients benefit from FOLFOX. Different subgroups of FOLFOX nonresponders may need to be treated differently.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Masculino , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico
7.
BMC Cancer ; 20(1): 952, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-33008336

RESUMO

BACKGROUND: Colorectal cancer (CRC) is the second most common cause of cancer-related mortality worldwide with one in every five patients diagnosed with metastatic CRC (mCRC). In mCRC cases, the 5-year survival rate remains at approximately 14%, reflecting the lack of effectiveness of currently available treatments such as the anti-VEGF targeting antibody Bevacizumab combined with the chemotherapy folinic acid, fluorouracil and oxaliplatin (FOLFOX). Approximately 60% of patients do not respond to this combined treatment. Furthermore, Bevacizumab inhibits dendritic cell (DC) maturation in poor responders, a key process for tumor eradication. METHOD: Following drug treatment, secreted expression levels of angiogenic and inflammatory markers in tumor conditioned media generated from human ex vivo colorectal tumors were measured by ELISA. Dendritic cell phenotypic and maturation markers were assessed by flow cytometry. RESULTS: Our novel compound, 1,4-dihydroxy quininib, acts in an alternative pathway compared to the approved therapy Bevacizumab. 1,4-dihydroxy quininib alone, and in combination with Bevacizumab or FOLFOX significantly reduced TIE-2 expression which is involved in the promotion of tumor vascularization. Combination treatment with 1,4-dihydroxy quininib significantly increased the expression level of DC phenotypic and maturation markers. CONCLUSION: Our results indicate the anti-angiogenic small molecule 1,4-dihydroxy quininib could be an alternative novel treatment in combination therapy for CRC patients.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/tratamento farmacológico , Idoso , Idoso de 80 Anos ou mais , Inibidores da Angiogênese/farmacologia , Angiopoietina-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Bevacizumab/administração & dosagem , Bevacizumab/farmacologia , Neoplasias Colorretais/irrigação sanguínea , Neoplasias Colorretais/metabolismo , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Humanos , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Compostos Organoplatínicos/farmacologia , Fenóis/administração & dosagem , Fenóis/farmacologia , Quinolinas/administração & dosagem , Quinolinas/farmacologia , Células Tumorais Cultivadas
8.
BMC Cancer ; 20(1): 633, 2020 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-32641104

RESUMO

BACKGROUND: Pancreatic cancer has a poor prognosis and few choices of therapy. For patients with adequate performance status, FOLFIRINOX or gemcitabine plus nab-paclitaxel are preferred first-line treatment. 5-Fluorouracil (5-FU)-based therapy (e.g. FOLFIRI, OFF, or FOLFOX) are often used in patients who previously received gemcitabine-based regimens. A systematic review was conducted of the safety and efficacy of FOLFOX for metastatic pancreatic cancer following prior gemcitabine-based therapy. A Bayesian fixed-effect meta-analysis with adjustment of patient performance status (PS) was conducted to evaluate overall survival (OS) and compare outcomes with nanoliposomal irinotecan combination therapy. METHODS: PubMed.gov , FDA.gov , ClinicalTrials.gov , congress abstracts, Cochrane.org library, and EMBASE database searches were conducted to identify randomized controlled trials of advanced/metastatic disease, prior gemcitabine-based therapy, and second-line treatment with 5-FU and oxaliplatin. The database search dates were January 1, 1990-June 30, 2019. Endpoints were OS and severe treatment-related adverse events (TRAEs). Trial-level PS scores were standardized by converting Karnofsky grade scores to Eastern Cooperative Oncology Group (ECOG) Grade, and overall study-weighted PS was calculated based on weighted average of all patients. RESULTS: Of 282 studies identified, 11 randomized controlled trials (N = 454) were included in the meta-analysis. Baseline weighted PS scores predicted OS in 10 of the 11 studies, and calculated PS scores of 1.0 were associated with a median OS of 6.3 months (95% posterior interval, 5.4-7.4). After adjusting for baseline PS, FOLFOX had a similar treatment effect profile (median OS, range 2.6-6.7 months) as 5-FU/leucovorin plus nanoliposomal irinotecan therapy (median OS, 6.1 months; 95% confidence interval 4.8-8.9). Neutropenia and fatigue were the most commonly reported Grade 3-4 TRAEs associated with FOLFOX. CONCLUSIONS: Baseline PS is a strong prognostic factor when interpreting the efficacy of 5-FU and oxaliplatin-based therapy of pancreatic cancer after progression on first-line gemcitabine-based regimens. When baseline PS is considered, FOLFOX has a similar treatment effect as 5-FU and nanoliposomal irinotecan therapy and a comparable safety profile. These findings suggest that 5-FU and oxaliplatin-based therapies remain an acceptable and alternative second-line treatment option for patients with pancreatic cancer and adequate PS (e.g. ECOG 0-1) following gemcitabine treatment.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/diagnóstico , Neoplasias Pancreáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Resistencia a Medicamentos Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/epidemiologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Avaliação de Estado de Karnofsky , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Neoplasias Pancreáticas/diagnóstico , Neoplasias Pancreáticas/mortalidade , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Análise de Sobrevida , Resultado do Tratamento
9.
Biosci Rep ; 40(7)2020 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-32677676

RESUMO

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide, and the mortality of patients with PDAC has not significantly decreased over the last few decades. Novel strategies exhibiting promising effects in preclinical or phase I/II clinical trials are often situated in an embarrassing condition owing to the disappointing results in phase III trials. The efficacy of the current therapeutic regimens is consistently compromised by the mechanisms of drug resistance at different levels, distinctly more intractable than several other solid tumours. In this review, the main mechanisms of drug resistance clinicians and investigators are dealing with during the exploitation and exploration of the anti-tumour effects of drugs in PDAC treatment are summarized. Corresponding measures to overcome these limitations are also discussed.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carcinoma Ductal Pancreático/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pancreáticas/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Carcinoma Ductal Pancreático/irrigação sanguínea , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/mortalidade , Hipóxia Celular , Ensaios Clínicos como Assunto , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Terapia de Alvo Molecular/efeitos adversos , Terapia de Alvo Molecular/métodos , Mutação , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Pâncreas/irrigação sanguínea , Pâncreas/efeitos dos fármacos , Pâncreas/patologia , Neoplasias Pancreáticas/irrigação sanguínea , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/mortalidade , Intervalo Livre de Progressão , Taxa de Sobrevida , Resultado do Tratamento , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética
10.
EBioMedicine ; 57: 102858, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32629389

RESUMO

BACKGROUND: A significant gap in pancreatic ductal adenocarcinoma (PDAC) patient's care is the lack of molecular parameters characterizing tumours and allowing a personalized treatment. METHODS: Patient-derived xenografts (PDX) were obtained from 76 consecutive PDAC and classified according to their histology into five groups. A PDAC molecular gradient (PAMG) was constructed from PDX transcriptomes recapitulating the five histological groups along a continuous gradient. The prognostic and predictive value for PMAG was evaluated in: i/ two independent series (n = 598) of resected tumours; ii/ 60 advanced tumours obtained by diagnostic EUS-guided biopsy needle flushing and iii/ on 28 biopsies from mFOLFIRINOX treated metastatic tumours. FINDINGS: A unique transcriptomic signature (PAGM) was generated with significant and independent prognostic value. PAMG significantly improves the characterization of PDAC heterogeneity compared to non-overlapping classifications as validated in 4 independent series of tumours (e.g. 308 consecutive resected PDAC, uHR=0.321 95% CI [0.207-0.5] and 60 locally-advanced or metastatic PDAC, uHR=0.308 95% CI [0.113-0.836]). The PAMG signature is also associated with progression under mFOLFIRINOX treatment (Pearson correlation to tumour response: -0.67, p-value < 0.001). INTERPRETATION: PAMG unify all PDAC pre-existing classifications inducing a shift in the actual paradigm of binary classifications towards a better characterization in a gradient. FUNDING: Project funding was provided by INCa (Grants number 2018-078 and 2018-079, BACAP BCB INCa_6294), Canceropole PACA, DGOS (labellisation SIRIC), Amidex Foundation, Fondation de France, INSERM and Ligue Contre le Cancer.


Assuntos
Adenocarcinoma/diagnóstico , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/diagnóstico , Transcriptoma/genética , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adolescente , Adulto , Idoso , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Intervalo Livre de Doença , Resistencia a Medicamentos Antineoplásicos/genética , Aspiração por Agulha Fina Guiada por Ultrassom Endoscópico , Feminino , Fluoruracila/efeitos adversos , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Xenoenxertos , Humanos , Irinotecano/efeitos adversos , Irinotecano/farmacologia , Leucovorina/efeitos adversos , Leucovorina/farmacologia , Masculino , Camundongos , Pessoa de Meia-Idade , Metástase Neoplásica , Oxaliplatina/efeitos adversos , Oxaliplatina/farmacologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Medicina de Precisão , Prognóstico , Adulto Jovem
11.
Curr Oncol ; 27(2): e222-e225, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32489272

RESUMO

At 9%, and 2% when diagnosed at advanced stage, the 5-year relative survival rate for pancreatic ductal adenocarcinoma (pdac) is the lowest of any cancer. The currently approved treatment options for metastatic pdac in the United States are folfirinox [irinotecan-fluorouracil (5fu)-leucovorin (lv)-oxaliplatin], gemcitabine-nab-paclitaxel, and liposomal irinotecan plus 5fu-lv. Liposomal irinotecan is a novel formulation of irinotecan encapsulated within a lipid bilayer, which favours local metabolic activation. The napoli-1 trial demonstrated the efficacy of liposomal irinotecan in combination with 5fu and lv for the treatment of advanced pdac after progression on gemcitabine-based chemotherapy. The 1-year survival in those patients was 25%; however, none had had irinotecan-refractory disease before treatment with liposomal irinotecan. Furthermore, the U.S. National Comprehensive Cancer Network guidelines recommend liposomal irinotecan plus 5fu-lv in patients who have received prior fluoropyrimidine-based therapy if no prior irinotecan therapy has been given. Here, we report a male patient with stage iv cancer of pancreas or bile duct (site unconfirmed) who experienced a prolonged (51 weeks) response to liposomal irinotecan plus 5fu-lv despite prior disease progression on irinotecan. Several factors have previously been associated with long-term survival in patients receiving liposomal irinotecan therapy: no prior irinotecan-based chemotherapy, high Karnofsky performance status score, age 65 years or less, serum carbohydrate antigen 19-9 less than 59 U/mL, neutrophil-to-lymphocyte ratio 5 or less, and absence of liver metastasis. The patient in the present report had none of those characteristics indicative of long-term survival, except his age at diagnosis-47 years.


Assuntos
Albuminas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias dos Ductos Biliares/tratamento farmacológico , Desoxicitidina/análogos & derivados , Irinotecano/uso terapêutico , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Albuminas/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Desoxicitidina/farmacologia , Desoxicitidina/uso terapêutico , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Irinotecano/farmacologia , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Paclitaxel/farmacologia
12.
Drugs ; 80(10): 1007-1018, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32557396

RESUMO

Liposomal irinotecan (nal-IRI; Onivyde®; also known as pegylated liposomal irinotecan) has been developed with the aim of maximising anti-tumour efficacy while minimising drug-related toxicities compared with the conventional (non-liposomal) formulation of this topoisomerase 1 inhibitor. In combination with 5-fluorouracil and leucovorin (5-FU/LV), nal-IRI is the first agent to be specifically approved for use in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) who have progressed following gemcitabine-based therapy. In the pivotal, phase III NAPOLI-1 trial, intravenous administration of nal-IRI + 5-FU/LV to gemcitabine-pretreated patients with mPDAC (as a second-line treatment in approximately two-thirds of cases) was associated with a significant ≈ 2-month median overall survival advantage compared with 5-FU/LV alone. Moreover, adding nal-IRI to 5-FU/LV extended survival with a manageable safety profile and without adversely affecting health-related quality of life, thereby producing significant and clinically meaningful gains in quality-adjusted survival relative to 5-FU/LV alone. Complementing the observed efficacy and safety of nal-IRI in NAPOLI-1 are an increasing number of real-world studies, which provide evidence of the effectiveness of this combination therapy in the treatment of mPDAC that has progressed following gemcitabine-based therapy in contemporary clinical practice in Europe, the USA and East Asia. Thus, nal-IRI, in combination with 5-FU/LV, is the first regimen specifically approved for use as a second- or subsequent-line therapy in gemcitabine-pretreated patients with mPDAC and, as such, represents a valuable treatment option in this setting.


Assuntos
Adenocarcinoma/tratamento farmacológico , Antineoplásicos/farmacologia , DNA Topoisomerases Tipo I/metabolismo , Irinotecano/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Inibidores da Topoisomerase I/farmacologia , Adenocarcinoma/metabolismo , Fluoruracila/farmacologia , Humanos , Leucovorina/farmacologia , Neoplasias Pancreáticas/metabolismo
13.
Biochim Biophys Acta Rev Cancer ; 1874(1): 188387, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32579889

RESUMO

Late detection, compromised immune system, and chemotherapy resistance underlie the poor patient prognosis for pancreatic ductal adenocarcinoma (PDAC) patients, making it the 3rd leading cause of cancer-related deaths in the United States. Cooperation between the tumor cells and the immune system leads to the immune escape and eventual establishment of the tumor. For more than 20 years, sincere efforts have been made to intercept the tumor-immune crosstalk and identify the probable therapeutic targets for breaking self-tolerance toward tumor antigens. However, the success of these studies depends on detailed examination and understanding of tumor-immune cell interactions, not only in the primary tumor but also at distant systemic niches. Innate and adaptive arms of the immune system sculpt tumor immunogenicity, where they not only aid in providing an amenable environment for their survival but also act as a driver for tumor relapse at primary or distant organ sites. This review article highlights the key events associated with tumor-immune communication and associated immunosuppression at both local and systemic microenvironments in PDAC. Furthermore, we discuss the approaches and benefits of targeting both local and systemic immunosuppression for PDAC patients. The present articles integrate data from clinical and genetic mouse model studies to provide a widespread consensus on the role of local and systemic immunosuppression in undermining the anti-tumor immune responses against PDAC.


Assuntos
Carcinoma Ductal Pancreático/terapia , Imunoterapia/métodos , Neoplasias Pancreáticas/terapia , Evasão Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Medula Óssea/efeitos dos fármacos , Medula Óssea/imunologia , Medula Óssea/patologia , Vacinas Anticâncer/administração & dosagem , Carcinoma Ductal Pancreático/imunologia , Carcinoma Ductal Pancreático/mortalidade , Carcinoma Ductal Pancreático/patologia , Quimioterapia Adjuvante/métodos , Ensaios Clínicos como Assunto , Terapia Combinada/métodos , Modelos Animais de Doenças , Intervalo Livre de Doença , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Imunidade Inata/efeitos dos fármacos , Irinotecano/farmacologia , Irinotecano/uso terapêutico , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Excisão de Linfonodo , Linfonodos/imunologia , Linfonodos/patologia , Linfonodos/cirurgia , Camundongos , Camundongos Transgênicos , Terapia Neoadjuvante/métodos , Oxaliplatina/farmacologia , Oxaliplatina/uso terapêutico , Pâncreas/imunologia , Pâncreas/patologia , Pâncreas/cirurgia , Pancreatectomia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Baço/imunologia , Baço/patologia , Baço/cirurgia , Esplenectomia , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/transplante , Transplante Autólogo/métodos
14.
Br J Cancer ; 123(3): 362-368, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32433600

RESUMO

BACKGROUND: Patients with borderline resectable pancreatic cancer (BRPC) have poor prognosis with upfront surgery. METHODS: This was a single-arm Phase 2 trial for clinical and biomarker analysis. The primary endpoint is 1-year progression-free survival (PFS) rate. Patients received 8 cycles of neoadjuvant modified (m) FOLFIRINOX. Up to 6 cycles of gemcitabine were given for patients who underwent surgery. Plasma immune cell subsets were measured for analysing correlations with overall survival (OS). RESULTS: Between May 2016 and March 2018, 44 chemotherapy- and radiotherapy-naïve patients with BRPC were included. With neoadjuvant mFOLFIRINOX, the objective response rate was 34.1%, and curative-intent surgery was done in 27 (61.4%) patients. With a median follow-up duration of 20.6 months (95% confidence interval [CI], 19.7-21.6 months), the median PFS and OS were 12.2 months (95% CI, 8.9-15.5 months) and 24.7 months (95% CI, 12.6-36.9), respectively. The 1-year PFS rate was 52.3% (95% CI, 37.6-67.0%). Higher CD14+ monocyte (quartile 4 vs 1-3) and lower CD69+ γδ T cell (γδ TCR+/CD69+) levels (quartiles 1-3 vs 4) were significantly associated with poor OS (p = 0.045 and p = 0.043, respectively). CONCLUSIONS: Neoadjuvant mFOLFIRINOX followed by postoperative gemcitabine were feasible and effective in BRPC patients. Monocyte and γδ T cells may have prognostic implications for patients with pancreatic cancer. ClinicalTrials.gov identifier: NCT02749136.


Assuntos
Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Biomarcadores Tumorais/imunologia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/imunologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígenos CD4/metabolismo , Desoxicitidina/administração & dosagem , Desoxicitidina/farmacologia , Esquema de Medicação , Estudos de Viabilidade , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/farmacologia , Humanos , Linfócitos Intraepiteliais/imunologia , Irinotecano/administração & dosagem , Irinotecano/farmacologia , Lectinas Tipo C/metabolismo , Leucovorina/administração & dosagem , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Terapia Neoadjuvante , Oxaliplatina/administração & dosagem , Oxaliplatina/farmacologia , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/cirurgia , Análise de Sobrevida , Resultado do Tratamento
15.
Chin J Nat Med ; 18(3): 178-185, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32245587

RESUMO

Enhanced glucose metabolism is one of the hallmarks of pancreatic cancer. MUC1, a transmembrane protein, is a global regulator of glucose metabolism and essential for progression of pancreatic cancer. To clarify the role of MUC1 in glucose metabolism, we knocked out MUC1 in Capan-1 and CFPAC-1 cells. MUC1 knockout (KO) cells uptook less glucose and secreted less lactate with a much lower proliferating rate. The mRNA level of key enzymes in glycolysis also decreased significantly in MUC1 KO cells. We also observed increased expression of breast cancer type 1 susceptibility protein (BRCA1) in MUC1 KO cells. Since BRCA1 has a strong inhibitory effect on glycolysis, we want to know whether the decreased glucose metabolism in MUC1 KO cells is due to increased BRCA1 expression. We treated wild type (WT) and MUC1 KO cells with BRCA1 inhibitor. BRCA1 inhibition significantly enhanced glucose uptake and lactate secretion in both WT and MUC1 KO cells. Expression of key enzymes in glycolysis also elevated after BRCA1 inhibition. Elevated glucose metabolism is known to facilitate cancer cells to gain chemoresistance. We treated MUC1 KO cells with gemcitabine and FOLFIRINOX in vitro and in vivo. The results showed that MUC1 KO sensitized pancreatic cancer cells to chemotherapy both in vitro and in vivo. In conclusion, we demonstrated that MUC1 promotes glycolysis through inhibiting BRCA1 expression. MUC1 may be a therapeutic target in pancreatic cancer treatment.


Assuntos
Proteína BRCA1/genética , Glucose/metabolismo , Glicólise , Mucina-1/metabolismo , Neoplasias Pancreáticas/metabolismo , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Desoxicitidina/análogos & derivados , Desoxicitidina/farmacologia , Fluoruracila/farmacologia , Regulação Neoplásica da Expressão Gênica , Técnicas de Inativação de Genes , Humanos , Irinotecano/farmacologia , Ácido Láctico/metabolismo , Leucovorina/farmacologia , Masculino , Camundongos Nus , Transplante de Neoplasias , Oxaliplatina/farmacologia , Neoplasias Pancreáticas/genética
16.
J BUON ; 25(1): 212-219, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32277634

RESUMO

Purpose: In patients with colorectal liver metastases (CLM) a long term survival and a probability of cure might be achieved with the surgical treatment of metastatic sites after prior application of systemic treatment. The purpose of this study was to assess the survival of patients with unresectable CLM treated with bevacizumab (bev) and FOLFOX4 (FOLFOX-bev) and to compare survival according to patient, disease and treatment characteristics. Methods: This research included 110 patients with unresectable CLM treated with FOLFOX-bev. Treatment response and resectability were estimated every 3 months. If resectability was achieved, patients were operated on and followed. Patient, disease and treatment characteristics in patients with and without hepatectomy were compared. Survival was estimated according to Kaplan-Meier method. Comparison of survival according to patient, disease and treatment characteristics was performed using log-rank test. Results: In patients with hepatectomy, treatment response was significantly more frequent (63, 63% vs 16, 66%, p<0.001). One- and three-year survival rate for the whole group was 87, 3% and 36, 1%, respectively; median overall survival (OS) was 23 months (95%CI 19, 63-28, 26). One- and three-year survival for patients with hepatectomy was 98, 48%, and 54, 76%, respectively; median OS was 35 months (95%CI 28, 83-41, 17). Three-year survival was significantly better in patients with hepatectomy (HR=3.775; 95%CI 2.150-6.627, p<0.001), older than 60 years (p=0.033), those without extrahepatic metastases (p=0.008) and those with treatment response (p=0.05). Conclusion: Significantly better survival had patients with hepatectomy, treatment response, older than 60 years and without extrahepatic metastases. FOLFOX4-bev is effective treatment for molecularly unselected patients.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/uso terapêutico , Neoplasias Colorretais/complicações , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/secundário , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Compostos Organoplatínicos/farmacologia , Compostos Organoplatínicos/uso terapêutico , Análise de Sobrevida , Resultado do Tratamento
17.
Clin Colorectal Cancer ; 19(2): 137-140, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32146081
18.
Anticancer Res ; 40(3): 1605-1611, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32132063

RESUMO

BACKGROUND/AIM: The aim of this study was to clarify the risk benefits of folinic acid, fluorouracil, and irinotecan (FOLFIRI) plus ramucirumab (F-RAM) as third-line and later-line treatment for metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: We compared the overall survival (OS), adverse events (AEs), and cost of F-RAM to those of trifluridine/tipiracil combination tablet (TAS-102). RESULTS: There was no significant difference in the median OS [6.1 (range=1.2-16.3) months vs. 6.1 (range=1.2-22.3) months; log-rank test, p=0.272] and treatment duration [4.0 (range=1.2-9.6) months vs. 3.5 (range=0.2-12.3) months, p=0.888] between the F-RAM (n=13) and the TAS-102 (n=36) groups. However, AEs were more frequent in the F-RAM group, and 1-year administration of F-RAM cost higher ($81,724.8 vs. $18,931.4, p<0.001). CONCLUSION: F-RAM as third-line and later-line treatment for mCRC has a poor risk benefit. TAS-102 should be given priority over F-RAM.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Fluoruracila/uso terapêutico , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Colorretais/mortalidade , Neoplasias Colorretais/patologia , Feminino , Fluoruracila/farmacologia , Humanos , Irinotecano/farmacologia , Leucovorina/farmacologia , Masculino , Pessoa de Meia-Idade , Taxa de Sobrevida
19.
J Recept Signal Transduct Res ; 40(3): 246-256, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32098568

RESUMO

An endless drug-resistant strains of Helicobacter pylori and multitudinous drug reactions are obstacles in the treatment of H. pylori infections, thereby ambitious novel proof-of-concept for inhibitor design was practiced in advancement of medication. Dihydropteroate synthase (DHPS) is an alluring target that plays a great role in folate synthesis pathway essential for amino acids biosynthesis was selected for designing novel drugs to prevent infections caused by pathogenic H. pylori. In the present study, a reliable tertiary structure of DHPS in complex with inhibitor 6MB was constructed by Modeler 9v19. DrugBank compounds of DHPS, published inhibitors, and co-crystal ligand (6MB) were docked against DHPS. The best docked compounds were screened against 28.5 million compounds resulted 1186 structural analogs. Virtual screening workflow and quantum polarized ligand dockings of these compounds against DHPS resulted three leads that showed better XP Gscores, ADME properties, and binding-free energies compared to 6MB, DrugBank compounds, and published inhibitors. The proposed leads were also validated by receiver operative characteristic (ROC) curve metrics in the presence of thousand decoys and the best docked existing compounds against DHPS. Long-range molecular dynamics (MD) simulations for 100 ns were executed after post-docking evaluations. Trajectory analysis showed the lead-DHPS docking complex's inter-molecular interactions were stable throughout the entire runtime of MD simulations than 6MB-DHPS complex and Eliglustat-DHPS complex. The study outcomes showed good competitive binding propensity and active-tunneling of leads over the existing inhibitors, thereby these leads could be ideal inhibitors against DHPS to target H. pylori.


Assuntos
Di-Hidropteroato Sintase/antagonistas & inibidores , Inibidores Enzimáticos/farmacologia , Helicobacter pylori/enzimologia , Sequência de Aminoácidos , Bases de Dados de Proteínas , Di-Hidropteroato Sintase/química , Di-Hidropteroato Sintase/metabolismo , Inibidores Enzimáticos/química , Helicobacter pylori/efeitos dos fármacos , Leucovorina/química , Leucovorina/farmacologia , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular
20.
Cancer Control ; 27(1): 1073274820902271, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32107929

RESUMO

BACKGROUND: The FIRE-3 phase III clinical trial demonstrated the marked advantage of prolonging the median overall survival of patients with final RAS wild-type (WT) left-sided metastatic colorectal cancer (mCRC) by 38.3 months after treatment with irinotecan, fluorouracil, and leucovorin (FOLFIRI) plus cetuximab and by 28.0 months after treatment with FOLFIRI plus bevacizumab. However, the substantial cost increase and economic impact of using cetuximab imposes a considerable burden on patients and society. METHODS: A Markov model based on the data collected in the FIRE-3 trial was developed to investigate the cost-effectiveness of treating patients with FOLFIRI plus either cetuximab or bevacizumab from the perspective of the Chinese health-care system. Costs, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) were calculated over a lifetime horizon. One-way and probabilistic sensitivity analyses were performed by varying potentially modifiable parameters. RESULTS: In our analysis, the total treatment costs in the bevacizumab and cetuximab groups were $92 549.31 and $94 987.31, respectively, and the QALYs gained were 1.58 and 2.05. In the base-case analysis, compared with bevacizumab, left-sided RAS WT patients receiving cetuximab gained 0.47 more QALYs at an ICER of $5187.23/QALY ($3166.23/LY). The 1-way sensitivity analysis showed that the most influential parameter was the cost of cetuximab. Probabilistic sensitivity analysis indicated that the cost-effective probability of cetuximab group was 92.8% under the willingness-to-pay threshold of $24 081. CONCLUSIONS: Treatment with FOLFIRI plus cetuximab in Chinese patients with left-sided RAS WT mCRC may improve health outcomes and use financial resources more efficiently than FOLFIRI plus bevacizumab.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/economia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Bevacizumab/economia , Bevacizumab/uso terapêutico , Camptotecina/análogos & derivados , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Bevacizumab/farmacologia , Camptotecina/economia , Camptotecina/farmacologia , Camptotecina/uso terapêutico , Cetuximab/farmacologia , Análise Custo-Benefício , Feminino , Fluoruracila/economia , Fluoruracila/farmacologia , Fluoruracila/uso terapêutico , Humanos , Leucovorina/economia , Leucovorina/farmacologia , Leucovorina/uso terapêutico , Masculino , Metástase Neoplásica
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