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1.
Int J Mol Sci ; 25(6)2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38542317

RESUMO

The probability of acute kidney injury (AKI) is higher in septic diabetic patients, which is associated with, among other factors, proximal tubular cell (PTC) injury induced by the hypoxic/hyperglycemic/inflammatory microenvironment that surrounds PTCs in these patients. Here, we exposed human PTCs (HK-2 cells) to 1% O2/25 mM glucose/inflammatory cytokines with the aim of studying the role of prostaglandin uptake transporter (PGT) and dipeptidyl peptidase-4 (DPP-4, a target of anti-hyperglycemic agents) as pharmacological targets to prevent AKI in septic diabetic patients. Our model reproduced two pathologically relevant mechanisms: (i) pro-inflammatory PTC activation, as demonstrated by the increased secretion of chemokines IL-8 and MCP-1 and the enhanced expression of DPP-4, intercellular leukocyte adhesion molecule-1 and cyclo-oxygenase-2 (COX-2), the latter resulting in a PGT-dependent increase in intracellular prostaglandin E2 (iPGE2); and (ii) epithelial monolayer injury and the consequent disturbance of paracellular permeability, which was related to cell detachment from collagen IV and the alteration of the cell cytoskeleton. Most of these changes were prevented by the antagonism of PGE2 receptors or the inhibition of COX-2, PGT or DPP-4, and further studies suggested that a COX-2/iPGE2/DPP-4 pathway mediates the pathogenic effects of the hypoxic/hyperglycemic/inflammatory conditions on PTCs. Therefore, inhibitors of PGT or DPP-4 ought to undergo testing as a novel therapeutic avenue to prevent proximal tubular damage in diabetic patients at risk of AKI.


Assuntos
Injúria Renal Aguda , Diabetes Mellitus , Inibidores da Dipeptidil Peptidase IV , Humanos , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus/tratamento farmacológico , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/prevenção & controle , Dipeptidil Peptidases e Tripeptidil Peptidases , Prostaglandinas , Inibidores da Dipeptidil Peptidase IV/farmacologia , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Dipeptidil Peptidase 4
2.
Ann Oncol ; 34(2): 186-199, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-36402300

RESUMO

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare and distinct entity within diffuse large B-cell lymphoma presenting with variable response rates probably to underlying molecular heterogeneity. PATIENTS AND METHODS: To identify and characterize PCNSL heterogeneity and facilitate clinical translation, we carried out a comprehensive multi-omic analysis [whole-exome sequencing, RNA sequencing (RNA-seq), methylation sequencing, and clinical features] in a discovery cohort of 147 fresh-frozen (FF) immunocompetent PCNSLs and a validation cohort of formalin-fixed, paraffin-embedded (FFPE) 93 PCNSLs with RNA-seq and clinico-radiological data. RESULTS: Consensus clustering of multi-omic data uncovered concordant classification of four robust, non-overlapping, prognostically significant clusters (CS). The CS1 and CS2 groups presented an immune-cold hypermethylated profile but a distinct clinical behavior. The 'immune-hot' CS4 group, enriched with mutations increasing the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) and nuclear factor-κB activity, had the most favorable clinical outcome, while the heterogeneous-immune CS3 group had the worse prognosis probably due to its association with meningeal infiltration and enriched HIST1H1E mutations. CS1 was characterized by high Polycomb repressive complex 2 activity and CDKN2A/B loss leading to higher proliferation activity. Integrated analysis on proposed targets suggests potential use of immune checkpoint inhibitors/JAK1 inhibitors for CS4, cyclin D-Cdk4,6 plus phosphoinositide 3-kinase (PI3K) inhibitors for CS1, lenalidomide/demethylating drugs for CS2, and enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) inhibitors for CS3. We developed an algorithm to identify the PCNSL subtypes using RNA-seq data from either FFPE or FF tissue. CONCLUSIONS: The integration of genome-wide data from multi-omic data revealed four molecular patterns in PCNSL with a distinctive prognostic impact that provides a basis for future clinical stratification and subtype-based targeted interventions.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Humanos , Fosfatidilinositol 3-Quinases/genética , Linfoma Difuso de Grandes Células B/patologia , Mutação , Complexo Repressor Polycomb 2/genética , Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/genética , Neoplasias do Sistema Nervoso Central/patologia
3.
Rev Neurol (Paris) ; 178(4): 377-384, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34556344

RESUMO

INTRODUCTION: Converting a high-volume primary stroke center (PSC) into a stroke center that can perform emergency endovascular treatment (EVT) could reduce the time to thrombectomy. We report the first results of a newly established EVT facility at the Perpignan PSC and their comparison with the targets defined by the established guidelines. PATIENTS AND METHOD: For this comprehensive observational study, data of patients with acute ischemic stroke (AIS) due to proximal large vessel occlusion (LVO) and treated by EVT at the Perpignan PSC from December 5, 2019 to September 15, 2020 were extracted from an ongoing prospective database. RESULTS: During the study period, 37 patients underwent EVT at the Perpignan PSC. The median (range) symptom-onset to recanalization time was 262min (100-485min). The median (range) intra-hospital times were: 20min (2-58min) for door-to-imaging, 57min (30-155min) for imaging-to-puncture, 55min (15-180min) for puncture-to-recanalization, and 137min (59-319min) for door-to-recanalization. At 3 months post-AIS, the favorable outcome (modified Ranking Score: 0-2) rate was 50% and the mortality rate was 19.4%. These results are comparable to those of previous clinical trials, and meet the targets defined by the current consensus statements for EVT. DISCUSSION AND CONCLUSION: Our results show the feasibility and safety of EVT in a PSC for patients with AIS due to LVO. The implementation of this strategy may be important for shortening the time to thrombectomy.


Assuntos
Isquemia Encefálica , Procedimentos Endovasculares , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/cirurgia , Procedimentos Endovasculares/métodos , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/cirurgia , Trombectomia/métodos , Tempo para o Tratamento , Resultado do Tratamento
4.
Rev Neurol (Paris) ; 178(10): 1079-1089, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36336491

RESUMO

BACKGROUND: Intravenous thrombolysis (IVT) use for acute ischemic stroke (AIS) varies among countries, partly due to guidelines and product labeling changes. The study aim was to identify the characteristics of patients with AIS treated with off-label IVT and to determine its safety when performed in a primary stroke center (PSC). METHODS: This observational, single-center study included all consecutive patients admitted to Perpignan PSC for AIS and treated with IVT and patients transferred for EVT, between January 1, 2015 and December 31, 2019. Data of patients treated with IVT according to ("in-label group") or outside ("off-label") the initial guidelines and manufacturer's product specification were compared. Safety was assessed using symptomatic intracerebral hemorrhage (SIH) as the main adverse event. RESULTS: Among the 892 patients in the database (834 screened by MRI, 93.5%), 746 were treated by IVT: 185 (24.8%) "in-label" and 561 (75.2%) "off-label". In the "off-label" group, 316 (42.4% of the cohort) had a single criterion for "off-label" use, 197 (26.4%) had two, and 48 (6.4%) had three or more criteria, without any difference in IVT safety pattern among them. SIH rates were comparable between the "off-label" and "in-label" groups (2.7% vs. 1.1%, P=0.21); early neurological deterioration and systematic adverse event due to IVT treatment were similar in the 2 groups. "Off-label" patients had higher in-hospital (8.7% vs. 3.8%, P=0.05) and 3-month mortality rates (12.1% vs 5.4%, P<0.01), but this is explained by confounding factors as they were older (76 vs 67 years, P<0.0001) and more dependent (median modified Rankin scale score 0.4 vs 0.1, P<0.0001) at admission. CONCLUSIONS: "Off-label" thrombolysis for AIS seems to be safe and effective in the routine setting of a primary stroke center.


Assuntos
Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Humanos , Terapia Trombolítica/efeitos adversos , Fibrinolíticos/efeitos adversos , Isquemia Encefálica/tratamento farmacológico , Estudos Retrospectivos , AVC Isquêmico/etiologia , Acidente Vascular Cerebral/terapia , Hemorragia Cerebral/induzido quimicamente , Hemorragia Cerebral/epidemiologia , Hemorragia Cerebral/tratamento farmacológico , Resultado do Tratamento
5.
J Neurooncol ; 148(3): 545-554, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32524392

RESUMO

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Sistema Nervoso Central/mortalidade , Quimiorradioterapia/mortalidade , Irradiação Craniana/mortalidade , Diagnóstico Tardio/estatística & dados numéricos , Imunocompetência , Linfoma não Hodgkin/mortalidade , Adulto , Idoso , Idoso de 80 Anos ou mais , Carmustina/administração & dosagem , Neoplasias do Sistema Nervoso Central/diagnóstico , Neoplasias do Sistema Nervoso Central/imunologia , Neoplasias do Sistema Nervoso Central/terapia , Citarabina/administração & dosagem , Feminino , Seguimentos , Humanos , Linfoma não Hodgkin/diagnóstico , Linfoma não Hodgkin/imunologia , Linfoma não Hodgkin/terapia , Masculino , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
6.
Oncologist ; 24(9): e898-e904, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-30867243

RESUMO

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a rare subtype of extranodal lymphoma. Despite established clinical prognostic scoring such as that of the Memorial Sloan Kettering Cancer Center (MSKCC) and the International Extranodal Lymphoma Study Group, outcome prediction needs to be improved. Several studies have indicated an association between changes in hematologic laboratory parameters with patient outcomes in PCNSL. We sought to assess the association between hematological parameters and overall survival (OS) in patients with PCNSL. METHODS: Pretreatment blood tests were analyzed in patients with newly diagnosed PCNSL (n = 182), and we divided the analysis into two cohorts (A and B, both n = 91). OS was evaluated using the Cox proportional hazards models and log-rank test. Furthermore, the accuracy of the different multivariate models was assessed by Harrell's concordance index (C-index). RESULTS: Using prechemotherapy blood tests, anemia was found in 38 patients (41.8%) in cohort A and 34 patients (37.4%) in cohort B. In univariate analysis, anemia (<12 g/dL in women and <13 g/dL in men) was significantly associated with OS. None of the other blood tests parameters (neutrophils, lymphocyte, or platelets counts) or their ratios (neutrophil-to-lymphocyte ratio and neutrophil-to-platelets ratio) were associated with OS. In multivariate analysis, after adjusting by MSKCC score, anemia remained an independent prognostic factor. Interestingly, the prediction accuracy of OS using Harrell's C-index was similar using anemia or MSKCC (mean C-index, 0.6) and was increased to 0.67 when combining anemia and MSKCC. CONCLUSION: The presence of anemia was associated with poor prognosis in both cohorts of PCNSL. Validation of these results and biologic role of hemoglobin levels in PCNSL requires further investigation. IMPLICATIONS FOR PRACTICE: The prediction of the outcome of primary central nervous system lymphoma (PCNSL) using the most frequently used scores (i.e., Memorial Sloan Kettering Cancer Center [MSKCC] or International Extranodal Lymphoma Study Group) needs to be improved. We analyzed a large cohort of PCNSL to dissect the potential prognostic value of blood tests in this rare entity. We found anemia as an independent predictor for overall survival in PCNSL. Interestingly, the accuracy to predict PCNSL outcome was improved using hemoglobin level. This improvement was additional to the currently used clinical score (i.e., MSKCC). Finally, none of the other blood tests parameters or their ratios had a prognostic impact in this study.


Assuntos
Anemia/sangue , Neoplasias do Sistema Nervoso Central/sangue , Hemoglobinas/metabolismo , Prognóstico , Idoso , Plaquetas/metabolismo , Plaquetas/patologia , Neoplasias do Sistema Nervoso Central/epidemiologia , Neoplasias do Sistema Nervoso Central/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfócitos/patologia , Masculino , Pessoa de Meia-Idade , Sistema Nervoso/metabolismo , Sistema Nervoso/patologia , Neutrófilos/patologia , Modelos de Riscos Proporcionais
7.
J Vasc Surg ; 70(5): 1642-1651, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-30926276

RESUMO

OBJECTIVE: New formulations and applications of hemostatic adjuncts such as fibrin sealant (FS) to support local hemostasis and sutures continue to be developed. In a pivotal, confirmatory, controlled, prospective, single-blinded, randomized, multicenter phase III clinical trial, the efficacy and safety of FS Grifols during vascular surgeries were evaluated. METHODS: Patients undergoing a nonemergency, open, peripheral vascular surgical procedure with moderate arterial bleeding were recruited. In an initial preliminary part of the study, all patients were treated with FS Grifols. In a subsequent primary part, patients were randomized (2:1) to FS Grifols or manual compression (MC). The primary efficacy end point was the proportion of the primary part patients achieving hemostasis by 4 minutes after the start of treatment. Cumulative proportion and time to hemostasis were secondary efficacy end points. Safety end points (in pooled preliminary and primary parts) included adverse events (AEs), vital signs, physical assessments, clinical laboratory tests, viral markers, and immunogenicity. RESULTS: The primary efficacy end point was met by 76.1% of patients (83/109) for the FS Grifols group versus 22.8% of patients (13/57) for the MC group (P < .001). The cumulative proportion of patients at 5, 7, and 10 minutes was 80.7%, 84.4%, and 88.1%, respectively, in the FS Grifols treatment group, and 28.1%, 35.1%, and 45.6% in the MC treatment group (P < .001). The median time to hemostasis was shorter in the FS Grifols group (4 minutes vs ≥10 minutes in the MC group; P < .001). The nature of AEs reported were those expected in the study patient profile. The percentage of patients experiencing treatment-emergent AEs were similar in both the FS Grifols (pooled n = 59 + 109) and MC groups (81.0% and 77.2%, respectively), most recurrent being procedural pain (34.5% and 36.8%, respectively) and pyrexia (11.3% and 10.5%, respectively). CONCLUSIONS: FS Grifols was superior in efficacy and similar in safety to MC as an adjunct local hemostatic agent in patients undergoing open vascular surgeries.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Adesivo Tecidual de Fibrina/administração & dosagem , Hemostasia Cirúrgica/métodos , Procedimentos Cirúrgicos Vasculares/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Feminino , Adesivo Tecidual de Fibrina/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Pressão , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
8.
Acta Oncol ; 57(3): 403-411, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29243538

RESUMO

BACKGROUND: Charcot Marie Tooth (CMT) disease is the most common form of hereditary neuropathy. Due to the high prevalence of mild and undiagnosed forms, patients with CMT disease may be exposed to severe neurotoxicity following the administration of neurotoxic chemotherapies. The aim of this report is to alert oncologists to the potential to precipitate severe irreversible peripheral neuropathies when administering neurotoxic compounds to undiagnosed CMT patients. MATERIAL AND METHODS: A retrospective research in the OncoNeuroTox database was performed (2010-2016), searching for patients with the diagnosis of chemotherapy-induced peripheral neuropathy (CIPN) and CMT disease. A comprehensive literature review for previously published cases was performed using the Pubmed and Cochrane databases (1972-2017). RESULTS: Among 428 patients with CIPN, we identified eight patients with concomitant CMT disease. Seven patients out of the eight had no previous diagnosis of CMT disease, although accurate familial history disclosed mild signs of peripheral neuropathy in five cases. Patients themselves had minor stigmata of long-standing peripheral damage. Patients received chemotherapy regimens based on vinca alkaloids, taxanes or a combination of vinca alkaloids and platinum compounds. In two cases, cumulative doses were below or equal to the expected neurotoxic threshold. Following chemotherapy administration, patients developed severe length-dependent sensory-motor deficits. Despite early drug discontinuation, most patients remained severely disabled. CONCLUSION: A brief checklist to disclose long-standing signs of peripheral neuropathy could be helpful to detect patients with undiagnosed hereditary neuropathies who could be at risk of developing severe irreversible neurotoxicity following the administration of neurotoxic agents.


Assuntos
Antineoplásicos/efeitos adversos , Doença de Charcot-Marie-Tooth/complicações , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Adulto , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto Jovem
9.
Biol Blood Marrow Transplant ; 23(1): 134-139, 2017 01.
Artigo em Inglês | MEDLINE | ID: mdl-27794456

RESUMO

We analyzed the incidence, clinical characteristics, prognostic factors, and outcome of central nervous system (CNS) infections in consecutive patients with receiving umbilical cord blood transplantation (UCBT) (n = 343) or HLA-matched sibling donor stem cell transplantation (MST) (n = 366). Thirty-four CNS infections were documented at a median time of 116 days after transplantation (range, 7 to 1161). The cumulative incidence (CI) risk of developing a CNS infection was .6% at day +30, 2.3% at day +90, and 4.9% at 5 years. The 5-year CI of CNS infection was 8.2% after UCBT and 1.7% after MST (P < .001). The causative micro-organisms of CNS infections were fungi (35%), virus (32%), Toxoplasma spp. (12%), and bacteria (12%). Fungal infections occurred in 11 patients after UCBT and 1 after MST and were due to Aspergillus spp. (n = 8), Cryptococcus neoformans (n = 2), Scedosporium prolificans (n = 1), and Mucor (n = 1). Except for 1 patient, all died from CNS fungal infection. Viral infections occurred in 9 patients after UCBT and 1 after MST and were due to human herpes virus 6 (n = 7), cytomegalovirus (n = 2), and varicella zoster virus (n = 1). CNS toxoplasmosis was diagnosed in 3 patients after UCBT and 1 after MST. Other pathogens were Staphylococcus spp, Nocardia spp, Streptococcus pneumoniae, and Mycobacterium tuberculosis. Twenty of the 34 patients (59%) died from the CNS infection. In multivariable analysis, UCBT and disease stage beyond first complete remission were independently associated with the risk of developing CNS infections. The 5-year overall survival was 19% in patients who developed a CNS and 39% for those who did not (P = .006). In conclusion, our study showed that CNS infections are a significant clinical problem after stem cell transplantation associated with poor survival. They were more frequent after UCBT compared to MST.


Assuntos
Infecções do Sistema Nervoso Central/etiologia , Transplante de Células-Tronco de Sangue do Cordão Umbilical/efeitos adversos , Antígenos HLA/análise , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Adolescente , Adulto , Idoso , Infecções Bacterianas/etiologia , Infecções do Sistema Nervoso Central/microbiologia , Infecções do Sistema Nervoso Central/mortalidade , Transplante de Células-Tronco de Sangue do Cordão Umbilical/métodos , Transplante de Células-Tronco de Sangue do Cordão Umbilical/mortalidade , Transplante de Células-Tronco Hematopoéticas/métodos , Transplante de Células-Tronco Hematopoéticas/mortalidade , Histocompatibilidade , Humanos , Incidência , Pessoa de Meia-Idade , Micoses/etiologia , Irmãos , Fatores de Tempo , Toxoplasmose/etiologia , Doadores não Relacionados , Viroses/etiologia , Adulto Jovem
10.
J Cancer Surviv ; 18(1): 59-67, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37142871

RESUMO

PURPOSE: Radiotherapy (RT) is a recognized risk factor for cerebrovascular (CV) disease in children and in adults with head and neck cancer. We aimed to investigate whether cerebral RT increases the risk of CV disease in adults with primary brain tumors (PBT). METHODS: We retrospectively identified adults with a supratentorial PBT diagnosed between 1975 and 2006 and with at least 10 years follow-up after treatment. We analyzed demographic, clinical, and radiological features with special attention to CV events. We also described CV events, vascular risk factors, and intracranial artery modifications in a cross-sectional study of irradiated patients alive at the time of the study. RESULTS: A total of 116 patients, treated with RT (exposed group), and 85 non-irradiated patients (unexposed group) were enrolled. Stroke was more frequent in irradiated PBT patients than in the unexposed group (42/116 (36%) vs 7/85 (8%); p < 0.001), with higher prevalence of both ischemic (27/116 (23%) vs 6/85 (7%); p = 0.004) and hemorrhagic (12/116 (10%) vs 1/85 (1%); p = 0.02) stroke. In the irradiated group, patients with tumors near the Willis Polygon were more likely to experience stroke (p < 0.016). Fourty-four alive irradiated patients were included in the cross-sectional study. In this subgroup, intracranial arterial stenosis was more prevalent (11/45, 24%) compared to general population (9%). CONCLUSIONS: Stroke prevalence is increased in long-surviving PBT patients treated with cranial RT. IMPLICATIONS FOR CANCER SURVIVORS: CV events are frequent in long survivors of PBT treated with cerebral RT. We propose a check list to guide management of late CV complications in adults treated with RT for PBT.


Assuntos
Neoplasias Encefálicas , Sobreviventes de Câncer , Neoplasias de Cabeça e Pescoço , Acidente Vascular Cerebral , Criança , Adulto , Humanos , Estudos Transversais , Estudos Retrospectivos , Acidente Vascular Cerebral/epidemiologia , Acidente Vascular Cerebral/etiologia , Neoplasias de Cabeça e Pescoço/complicações , Neoplasias Encefálicas/epidemiologia , Neoplasias Encefálicas/radioterapia
11.
Biochim Biophys Acta Mol Basis Dis ; 1866(7): 165795, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-32278009

RESUMO

Cisplatin's toxicity in renal tubular epithelial cells limits the therapeutic efficacy of this antineoplastic drug. In cultured human proximal tubular HK-2 cells (PTC) a prostaglandin uptake transporter (PGT)-dependent increase in intracellular prostaglandin E2 (iPGE2) mediates cisplatin's toxicity (i.e. increased cell death and loss of cell proliferation) so that it is prevented by PGT inhibitors. Here we found in cisplatin-treated PTC that 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), a PGT inhibitor, prevented cisplatin's toxicity but not the increase in iPGE2. Because expression of retinoic acid receptor-ß (RAR-ß) is dependent on iPGE2 and because RAR-ß is a regulator of cell survival and proliferation, we hypothesized that RAR-ß might mediate the protective effect of DIDS against cisplatin's toxicity in PTC. Our results confirmed this hypothesis because: i) protection of PTC by DIDS was abolished by RAR-ß antagonist LE-135; ii) DIDS increased the expression of RAR-ß in PTC and prevented its decrease in cisplatin-treated PTC but not in cisplatin-treated human cervical adenocarcinoma HeLa cells in which DIDS failed to prevent cisplatin's toxicity; iii) while RAR-ß expression decreased in cisplatin-treated PTC, RAR-ß over-expression prevented cisplatin's toxicity. RAR-ß agonist CH55 or RAR pan-agonist all-trans retinoic acid did not prevent cisplatin's toxicity, which suggests that RAR-ß does not protect PTC through activation of gene transcription. In conclusion, RAR-ß might be a new player in cisplatin-induced proximal tubular injury and the preservation of its expression in proximal tubules through treatment with DIDS might represent a novel strategy in the prevention of cisplatin's nephrotoxicity without compromising cisplatin's chemotherapeutic effect on cancer cells.


Assuntos
Adenocarcinoma/tratamento farmacológico , Cisplatino/efeitos adversos , Dinoprostona/genética , Receptores do Ácido Retinoico/genética , Neoplasias do Colo do Útero/tratamento farmacológico , Ácido 4,4'-Di-Isotiocianoestilbeno-2,2'-Dissulfônico/farmacologia , Adenocarcinoma/genética , Adenocarcinoma/patologia , Antineoplásicos/efeitos adversos , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Chalconas/farmacologia , Cisplatino/farmacologia , Dibenzazepinas/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HeLa , Humanos , Túbulos Renais Proximais/efeitos dos fármacos , Substâncias Protetoras , Transdução de Sinais/efeitos dos fármacos , Neoplasias do Colo do Útero/genética , Neoplasias do Colo do Útero/patologia
12.
J Invest Surg ; 33(3): 218-230, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30303427

RESUMO

BACKGROUND/PURPOSE: Rapid hemostasis, an essential prerequisite of good surgical practice during surgical bleeding, including soft tissue open surgery, often requires adjunctive treatment. We evaluated the safety and hemostatic effectiveness of a human plasma-derived fibrin sealant (FS Grifols) in soft tissue open surgery. METHODS: Patients with moderate soft tissue bleeding during open, urologic, gynecologic or general surgery were studied. The trial consisted of a preliminary phase (to familiarize investigators with the technique for FS Grifols application and the intraoperative procedures required by the clinical protocol) and a primary phase: in both phases, patients were randomized 1:1 to FS Grifols or Surgicel®. The primary efficacy endpoint, based on analysis of subjects in the primary phase of the study, was to evaluate whether FS Grifols was non-inferior to Surgicel® in achieving hemostasis, based on the proportion of subjects in both treatment groups who achieved hemostasis at the target bleeding site (TBS) by 4 min (T4) following the start of treatment application. Safety assessments included adverse events (AEs), vital signs, physical assessments, common clinical laboratory tests, viral markers, and immunogenicity. RESULTS: A total of 224 subjects were randomized (primary phase): FS Grifols (N = 116), Surgicel® (N = 108). The 95% CI at T4 for the ratio of the proportion of patients achieving hemostasis in the two treatment groups was 1.064 (0.934, 1.213), indicating non-inferiority for FS Grifols vs. Surgicel®. The rate of hemostasis at the TBS by T4 in both phases of the study was higher in the FS Grifols treatment group (preliminary phase: 90.2%; primary phase: 82.8%) than in the Surgicel® treatment group (preliminary phase: 78.8%; primary phase: 77.8%). Overall, reported AEs were as expected in surgical patients and were similar between the two treatment groups. CONCLUSIONS: This study shows the non-inferiority in time to hemostasis of FS Grifols vs. Surgicel as an adjunct to hemostasis in patients undergoing soft tissue open surgery, and a similar rate of AEs.


Assuntos
Perda Sanguínea Cirúrgica/prevenção & controle , Celulose Oxidada/administração & dosagem , Adesivo Tecidual de Fibrina/administração & dosagem , Hemostasia Cirúrgica/métodos , Hemostáticos/administração & dosagem , Procedimentos Cirúrgicos Operatórios/efeitos adversos , Adulto , Idoso , Perda Sanguínea Cirúrgica/estatística & dados numéricos , Celulose Oxidada/efeitos adversos , Feminino , Adesivo Tecidual de Fibrina/efeitos adversos , Hemostasia Cirúrgica/efeitos adversos , Hemostáticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Método Simples-Cego , Resultado do Tratamento , Adulto Jovem
14.
Clin Neurol Neurosurg ; 163: 167-172, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29121544

RESUMO

OBJECTIVES: Ocular flutter (OF) and opsoclonus are considered a continuum with a similar pathogenesis. Due to the rarity of this disease in the adult population, little is known about the brain morphological changes in the chronic phase of the disease. PATIENTS AND METHODS: Six magnetic resonance imaging from adults with previous history of OF/Opsoclonus and 12 healthy patients (paired by age and sex) were analyzed in order to identify the long term cortical thickness pattern in this rare disease by using Freesurfer. RESULTS: Patients with OF/Opsoclonus showed reduced cerebellum cortical volume with a subsequent diminution in total cerebellar volume. White mater cerebellum volume was not modified. In addition, we have also identified a significant supratentorial gray matter volume decrease in OF/Opsoclonus patients, involving both the cortical and the subcortical gray matter. CONCLUSIONS: OF/Opsoclonus in adults may be associated with cortical and subcortical gray matter atrophy, as well as decreased cerebellar cortical volume. Further larger prospective studies are necessary to confirm these results.


Assuntos
Cerebelo/patologia , Transtornos da Motilidade Ocular/patologia , Síndrome de Opsoclonia-Mioclonia/patologia , Adulto , Atrofia , Feminino , Substância Cinzenta/patologia , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Transtornos da Motilidade Ocular/diagnóstico , Síndrome de Opsoclonia-Mioclonia/diagnóstico , Estudos Prospectivos , Movimentos Sacádicos
15.
Rev Neurol ; 56(3): 137-42, 2013 Feb 01.
Artigo em Espanhol | MEDLINE | ID: mdl-23359074

RESUMO

INTRODUCTION: Carotid stenosis is a complication of cervical radiotherapy. In these cases carotid angioplasty has been considered as the elective revascularisation treatment. Yet, the indication to treat is under discussion due to the high rate of restenosis and the scarcity of studies conducted on the long-term development. AIMS: To report on a series of patients with carotid stenosis following radiotherapy who were treated by means of angioplasty, the aim being to analyse their long- and short-term development. PATIENTS AND METHODS: Of a series of 426 patients with carotid stenosis treated by endovascular means, 12 of them (2.8%) had previously received radiotherapy in the neck. All of them were submitted to a clinical and imaging follow-up. Data were collected concerning the rate of complications during the first four weeks and in the long term, as well as the rate of restenosis in the follow-up. RESULTS: The mean interval between radiotherapy and the detection of stenosis was 14.7 years. Ten patients (83.3%) were symptomatic. No complications occurred during the first four weeks following the angioplasty. The mean follow-up time was 45.09 months: 16.7% of patients presented a stroke, 8.3% suffered acute myocardial infarction and 33.3% died (16.6% due to cancer). At least six patients (50%) were diagnosed with restenosis, all equal to or greater than 50% and none of them were symptomatic. CONCLUSIONS: Carotid angioplasty is a safe, effective technique in stenosis following radiotherapy, with few short-term complications. The rate of carotid restenosis is high. The main cause of death is cancer.


Assuntos
Angioplastia , Lesões das Artérias Carótidas/etiologia , Estenose das Carótidas/cirurgia , Lesões por Radiação/cirurgia , Radioterapia/efeitos adversos , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/etiologia , Carcinoma/radioterapia , Estenose das Carótidas/etiologia , Feminino , Neoplasias de Cabeça e Pescoço/radioterapia , Humanos , Neoplasias Laríngeas/radioterapia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Lesões por Radiação/etiologia , Recidiva , Stents
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