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1.
Int J Mol Sci ; 22(12)2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-34200673

RESUMO

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune-biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.


Assuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Autoimunidade , Antígenos HLA/imunologia , Miastenia Gravis/patologia , Miosite/patologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Humanos , Masculino , Miastenia Gravis/induzido quimicamente , Miastenia Gravis/imunologia , Miosite/induzido quimicamente , Miosite/imunologia , Prognóstico
2.
Front Immunol ; 12: 613070, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815368

RESUMO

Lack of specific antiviral treatment for COVID-19 has resulted in long hospitalizations and high mortality rate. By harnessing the regulatory effects of adenosine on inflammatory mediators, we have instituted a new therapeutic treatment with inhaled adenosine in COVID-19 patients, with the aim of reducing inflammation, the onset of cytokine storm, and therefore to improve prognosis. The use of inhaled adenosine in COVID19 patients has allowed reduction of length of stay, on average 6 days. This result is strengthened by the decrease in SARS-CoV-2 positive days. In treated patients compared to control, a clear improvement in PaO2/FiO2 was observed together with a reduction in inflammation parameters, such as the decrease of CRP level. Furthermore, the efficacy of inhaled exogenous adenosine led to an improvement of the prognosis indices, NLR and PLR. The treatment seems to be safe and modulates the immune system, allowing an effective response against the viral infection progression, reducing length of stay and inflammation parameters.


Assuntos
Adenosina/farmacologia , COVID-19/tratamento farmacológico , Adenosina/uso terapêutico , Adulto , Idoso , Antibacterianos/administração & dosagem , Azitromicina/administração & dosagem , COVID-19/diagnóstico por imagem , COVID-19/fisiopatologia , Estudos de Casos e Controles , Inibidores do Citocromo P-450 CYP3A/administração & dosagem , Síndrome da Liberação de Citocina/fisiopatologia , Inibidores Enzimáticos/administração & dosagem , Feminino , Heparina/administração & dosagem , Hospitalização , Humanos , Hidroxicloroquina/administração & dosagem , Inflamação/tratamento farmacológico , Lopinavir/administração & dosagem , Masculino , Pessoa de Meia-Idade , Prognóstico , Tomografia Computadorizada por Raios X
3.
PLoS One ; 15(10): e0239692, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33031409

RESUMO

BACKGROUND: SARS-Cov2 infection may trigger lung inflammation and acute-respiratory-distress-syndrome (ARDS) that requires active ventilation and may have fatal outcome. Considering the severity of the disease and the lack of active treatments, 14 patients with Covid-19 and severe lung inflammation received inhaled adenosine in the attempt to therapeutically compensate for the oxygen-related loss of the endogenous adenosine→A2A adenosine receptor (A2AR)-mediated mitigation of the lung-destructing inflammatory damage. This off label-treatment was based on preclinical studies in mice with LPS-induced ARDS, where inhaled adenosine/A2AR agonists protected oxygenated lungs from the deadly inflammatory damage. The treatment was allowed, considering that adenosine has several clinical applications. PATIENTS AND TREATMENT: Fourteen consecutively enrolled patients with Covid19-related interstitial pneumonitis and PaO2/FiO2 ratio<300 received off-label-treatment with 9 mg inhaled adenosine every 12 hours in the first 24 hours and subsequently, every 24 days for the next 4 days. Fifty-two patients with analogue features and hospitalized between February and April 2020, who did not receive adenosine, were considered as a historical control group. Patients monitoring also included hemodynamic/hematochemical studies, CTscans, and SARS-CoV2-tests. RESULTS: The treatment was well tolerated with no hemodynamic change and one case of moderate bronchospasm. A significant increase (> 30%) in the PaO2/FiO2-ratio was reported in 13 out of 14 patients treated with adenosine compared with that observed in 7 out of52 patients in the control within 15 days. Additionally, we recorded a mean PaO2/FiO2-ratio increase (215 ± 45 vs. 464 ± 136, P = 0.0002) in patients receiving adenosine and no change in the control group (210±75 vs. 250±85 at 120 hours, P>0.05). A radiological response was demonstrated in 7 patients who received adenosine, while SARS-CoV-2 RNA load rapidly decreased in 13 cases within 7 days while no changes were recorded in the control group within 15 days. There was one Covid-19 related death in the experimental group and 11in the control group. CONCLUSION: Our short-term analysis suggests the overall safety and beneficial therapeutic effect of inhaled adenosine in patients with Covid-19-inflammatory lung disease suggesting further investigation in controlled clinical trials.


Assuntos
Adenosina/efeitos adversos , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adenosina/administração & dosagem , Administração por Inalação , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/patologia , Infecções por Coronavirus/fisiopatologia , Feminino , Hospitalização , Humanos , Pulmão/patologia , Pulmão/virologia , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/virologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Pneumonia Viral/fisiopatologia , Estudos Retrospectivos , SARS-CoV-2
4.
Cells ; 9(9)2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32854442

RESUMO

Tumor-infiltrating T cell rescue by programmed cell death receptor-1 (PD-1)/PD-1 ligand-1 (PD-L1) immune checkpoint blockade is a recommended treatment for malignant diseases, including metastatic non-small-cell lung cancer (mNSCLC), malignant melanoma (MM), head and neck, kidney, and urothelial cancer. Monoclonal antibodies (mAbs) against either PD-1 or PD-L1 are active agents for these patients; however, their use may be complicated by unpredictable immune-related adverse events (irAEs), including immune-related pneumonitis (IRP). We carried out a retrospective multi-institutional statistical analysis to investigate clinical and biological parameters correlated with IRP rate on a cohort of 256 patients who received real-world treatment with PD-1/PD-L1 blocking mAbs. An independent radiological review board detected IRP in 29 patients. We did not find statistical IRP rate correlation with gender, tumor type, specific PD-1 or PD-L1 blocking mAbs, radiation therapy, inflammatory profile, or different irAEs. A higher IRP risk was detected only in mNSCLC patients who received metronomic chemotherapy +/- bevacizumab compared with other treatments prior PD-1/PD-L1 blockade. Moreover, we detected a strong correlation among the IRP rate and germinal expression of HLA-B*35 and DRB1*11, alleles associated to autoimmune diseases. Our findings may have relevant implications in predicting the IRP rate in mNSCLC patients receiving PD-1/PD-L1 blockade and need to be validated on a larger patient series.


Assuntos
Genes MHC Classe I/genética , Inibidores de Checkpoint Imunológico/efeitos adversos , Imunoterapia/métodos , Pneumonia/induzido quimicamente , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
5.
Clin Pharmacol Ther ; 106(2): 422-431, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30739312

RESUMO

Taxane-related peripheral neuropathy (TrPN) is a dose-limiting toxicity with important interindividual variability. Genetic polymorphisms in absorption, distribution, metabolism, and excretion (ADME) genes may account for variability in drug efficacy and/or toxicity. By the use of Affymetrix drug-metabolizing enzyme and transporter microarray platform, in a retrospective case-control study, the correlation between ADME polymorphic variants and grades ≥ 2-3-TrPN was investigated. In a breast cancer (BC) training set, five single-nucleotide polymorphisms in NR1I3 and UDP-glucuronosyltransferase (UGT)2B7 genes were correlated to grades ≥ 2-3-TrPN protection. By receiver operating characteristic curves, the grades ≥ 2-3-TrPN-related candidate biomarkers in an independent series of 54 patients with BC (17 cases and 37 controls) were validated. NR1I3 was correlated to paclitaxel-TrPN and UGT2B7 to docetaxel-TrPN. Moreover, a genetic signature of prognostic relevance for BC outcome was found. Our findings might have potential relevance for personalized management of patients with BC for prevention of treatment failure in ultrametabolizer genetic variants.


Assuntos
Neoplasias da Mama , Docetaxel , Glucuronosiltransferase/genética , Paclitaxel , Doenças do Sistema Nervoso Periférico , Receptores Citoplasmáticos e Nucleares/genética , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Biomarcadores Farmacológicos/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Estudos de Casos e Controles , Docetaxel/administração & dosagem , Docetaxel/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/genética , Doenças do Sistema Nervoso Periférico/prevenção & controle , Testes Farmacogenômicos/métodos , Polimorfismo de Nucleotídeo Único , Prognóstico
6.
Crit Rev Oncol Hematol ; 131: 83-89, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30293710

RESUMO

INTRODUCTION: Carboplatin is the milestone of epithelial ovarian cancer (EOC) treatment, thus response to platinum is the major prognostic factor. Among platinum-sensitive patients, 40% carry a germline or somatic BRCA1/2 mutation. In this scenario a new class of drugs, the PARP inhibitors (PARPis), produced a significant improvement in long-term disease control. In order to make an aggregate evaluation of the impact of these agents, we performed a systematic review and meta-analysis. PATIENTS AND METHODS: Clinical trials were selected by searching "Pubmed" database and abstracts from major cancer meetings. We considered the January 2008 - April 2018 time frame. Progression free survival (PFS) was the primary end-point, toxicities were secondary end-points. Hazard ratios (HRs) of PFS, with confidence intervals, and risk ratios of grade 3-4 toxicity rates, were extracted from retrieved studies and included in the current analysis. Meta-analysis was carried out by the fixed and random effect models. We conducted this meta-analysis to also compare indirectly the efficacy of different PARPis in EOC patients. RESULTS: Five randomized trials for a total of 1839 patients were selected and included in the final analysis. In particular, we evaluated a BRCA-mutant cohort (871 patients) with a pooled HR 0.25 (95%CI 0.21-0.31) and the BRCA-wild type cohort (836 patients) with a pooled HR 0.41 (95%CI 0.31-0.55), respectively. Regarding safety profile, no significant differences were detected in all grade toxicities, however, taking into account 3-4 grade toxicities and SAEs (severe adverse events), we show that rucaparib-treated patients reported major abdominal pain events, while niraparib-treated patients were associated with the highest percentage of haematological toxicities, hypothesizing a drug effect for the safety analysis. In the indirect comparisons, significant differences were not detected on PFS for the different agents. CONCLUSIONS: We confirm a significant benefit in survival outcome of PARPis for EOC patients with a "class effect" on the bases of narrow CI and indirect comparisons in the different groups. Therefore, we underline that this strategy is of special value in BRCA-mutated patients because genetic testing allows best patient selection for all PARPis with the added value of individualized prevention in familiars.


Assuntos
Neoplasias Ovarianas/tratamento farmacológico , Poli(ADP-Ribose) Polimerase-1/antagonistas & inibidores , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Feminino , Humanos , Prognóstico
7.
Cancer Chemother Pharmacol ; 77(1): 205-9, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26607259

RESUMO

PURPOSE: Erlotinib is a targeted agent commonly used in advanced non-small cell lung cancer (aNSCLC). However, drug-related skin toxicity often may affect the quality of life of cancer patients and lead to treatment discontinuation. Genetic polymorphisms in drug transporters and metabolizing enzymes play a major role in the interindividual variability in terms of efficacy and toxicity of erlotinib treatment. The aim of our study was to identify genetic determinants in adsorption, distribution, metabolism, and excretion genes influencing skin rash (SR) by the novel drug-metabolizing enzyme and transporter (DMET) microarray Affymetrix platform in aNSCLC patients. METHODS: In a retrospective study, 34 erlotinib-treated aNSCLC patients were genotyped by DMET Plus chip: 23 patients experienced SR (cases), while 11 patients did not (controls). Peripheral blood DNA was genotyped. Genotype association was analyzed by Fisher's exact test, and the toxicity-associated gene sets underwent Ingenuity Pathway Analysis (IPA). RESULTS: Seven SNPs in six genes (CYP27B1, MAT1A1, CHST1, CYP4B1, ADH6, and SLC22A1) were associated with the occurrence of SR or with a protective effect. Specifically, the rs8176345 in CYP27B1 gene was significantly correlated with SR (p = 0.0003, OR 55.55, 95% CI 2.7036-1141.1707). The IPA on SR-related genes highlighted the role of a variety of canonical pathways including 1,25-dihydroxyvitamin D3 biosynthesis, S-adenosyl-L-methionine biosynthesis, and methionine degradation I (to homocysteine) in SR development. CONCLUSION: Although exploratory, this study indicates rs8176345 in CYP27B1 gene as significantly correlated with erlotinib-induced SR in aNSCLC patients probably through a mechanism mediated by vitamin D3 and inflammation at skin level.


Assuntos
25-Hidroxivitamina D3 1-alfa-Hidroxilase/genética , Antineoplásicos/efeitos adversos , Erupção por Droga/etiologia , Cloridrato de Erlotinib/efeitos adversos , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Idoso , Antineoplásicos/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Colecalciferol/metabolismo , Erupção por Droga/genética , Cloridrato de Erlotinib/uso terapêutico , Feminino , Genótipo , Humanos , Inflamação/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Qualidade de Vida , Estudos Retrospectivos
8.
J Cell Physiol ; 228(7): 1506-15, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23254643

RESUMO

Skeletal homeostasis relies upon a fine tuning of osteoclast (OCL)-mediated bone resorption and osteoblast (OBL)-dependent bone formation. This balance is unsettled by multiple myeloma (MM) cells, which impair OBL function and stimulate OCLs to generate lytic lesions. Emerging experimental evidence is disclosing a key regulatory role of microRNAs (miRNAs) in the regulation of bone homeostasis suggesting the miRNA network as potential novel target for the treatment of MM-related bone disease (BD). Here, we report that miR-29b expression decreases progressively during human OCL differentiation in vitro. We found that lentiviral transduction of miR-29b into OCLs, even in the presence of MM cells, significantly impairs tartrate acid phosphatase (TRAcP) expression, lacunae generation, and collagen degradation, which are relevant hallmarks of OCL activity. Accordingly, expression of cathepsin K and metalloproteinase 9 (MMP9) as well as actin ring rearrangement were impaired in the presence of miR-29b. Moreover, we found that canonical targets C-FOS and metalloproteinase 2 are suppressed by constitutive miR-29b expression which also downregulated the master OCL transcription factor, NAFTc-1. Overall, these data indicate that enforced expression of miR-29b impairs OCL differentiation and overcomes OCL activation triggered by MM cells, providing a rationale for miR-29b-based treatment of MM-related BD.


Assuntos
MicroRNAs/genética , MicroRNAs/metabolismo , Mieloma Múltiplo/terapia , Osteoclastos/metabolismo , Osteoclastos/patologia , Osteólise/terapia , Fosfatase Ácida/metabolismo , Actinas/metabolismo , Reabsorção Óssea/etiologia , Reabsorção Óssea/genética , Reabsorção Óssea/prevenção & controle , Catepsina K/metabolismo , Diferenciação Celular , Linhagem Celular Tumoral , Células Cultivadas , Colágeno Tipo I/metabolismo , Expressão Gênica , Genes fos , Humanos , Isoenzimas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , MicroRNAs/uso terapêutico , Mieloma Múltiplo/complicações , Mieloma Múltiplo/metabolismo , Fatores de Transcrição NFATC/metabolismo , Osteoblastos/metabolismo , Osteoblastos/patologia , Osteólise/etiologia , Osteólise/metabolismo , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , Fosfatase Ácida Resistente a Tartarato
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