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1.
BMJ Case Rep ; 14(1)2021 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-33431539

RESUMO

We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.


Assuntos
/complicações , Glucocorticoides/uso terapêutico , Rejeição de Enxerto/prevenção & controle , Imunossupressores/uso terapêutico , Transplante de Rim , Transplante de Pâncreas , Paraplegia/complicações , Acidentes de Trânsito , Asma/complicações , /fisiopatologia , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/cirurgia , Everolimo/uso terapêutico , Febre/fisiopatologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Hipotensão/fisiopatologia , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
2.
Cochrane Database Syst Rev ; 10: CD012796, 2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33058158

RESUMO

BACKGROUND: Several comparative randomised controlled trials (RCTs) have been performed including combinations of tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors since the publication of a Cochrane Review on targeted therapy for metastatic renal cell carcinoma (mRCC) in 2008. This review represents an update of that original review. OBJECTIVES: To assess the effects of targeted therapies for clear cell mRCC in patients naïve to systemic therapy. SEARCH METHODS: We performed a comprehensive search with no restrictions on language or publication status. The date of the latest search was 18 June 2020. SELECTION CRITERIA: We included randomised controlled trials, recruiting patients with clear cell mRCC naïve to previous systemic treatment. The index intervention was any TKI-based targeted therapy. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the included studies and extracted data for the primary outcomes: progression-free survival (PFS), overall survival (OS) and serious adverse events (SAEs); and the secondary outcomes: health-related quality of life (QoL), response rate and minor adverse events (AEs). We performed statistical analyses using a random-effects model and rated the certainty of evidence according to the GRADE approach. MAIN RESULTS: We included 18 RCTs reporting on 11,590 participants randomised across 18 comparisons. This abstract focuses on the primary outcomes of select comparisons. 1. Pazopanib versus sunitinib Pazopanib may result in little to no difference in PFS as compared to sunitinib (hazard ratio (HR) 1.05, 95% confidence interval (CI) 0.90 to 1.23; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 420 per 1000 in this trial at 12 months, this corresponds to 18 fewer participants experiencing PFS (95% CI 76 fewer to 38 more) per 1000 participants. Pazopanib may result in little to no difference in OS compared to sunitinib (HR 0.92, 95% CI 0.80 to 1.06; 1 study, 1110 participants; low-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 27 more OSs (95% CI 19 fewer to 70 more) per 1000 participants. Pazopanib may result in little to no difference in SAEs as compared to sunitinib (risk ratio (RR) 1.01, 95% CI 0.94 to 1.09; 1 study, 1102 participants; low-certainty evidence). Based on the control event risk of 734 per 1000 in this trial, this corresponds to 7 more participants experiencing SAEs (95% CI 44 fewer to 66 more) per 1000 participants. 2. Sunitinib versus avelumab and axitinib Sunitinib probably reduces PFS as compared to avelumab plus axitinib (HR 1.45, 95% CI 1.17 to 1.80; 1 study, 886 participants; moderate-certainty evidence). Based on the control event risk of 550 per 1000 in this trial at 12 months, this corresponds to 130 fewer participants experiencing PFS (95% CI 209 fewer to 53 fewer) per 1000 participants. Sunitinib may result in little to no difference in OS (HR 1.28, 95% CI 0.92 to 1.79; 1 study, 886 participants; low-certainty evidence). Based on the control event risk of 890 per 1000 in this trial at 12 months, this would result in 29 fewer OSs (95% CI 78 fewer to 8 more) per 1000 participants. Sunitinib may result in little to no difference in SAEs (RR 1.01, 95% CI 0.93 to 1.10; 1 study, 873 participants; low-certainty evidence). Based on the control event risk of 705 per 1000 in this trial, this corresponds to 7 more SAEs (95% CI 49 fewer to 71 more) per 1000 participants.  3. Sunitinib versus pembrolizumab and axitinib Sunitinib probably reduces PFS as compared to pembrolizumab plus axitinib (HR 1.45, 95% CI 1.19 to 1.76; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 590 per 1000 in this trial at 12 months, this corresponds to 125 fewer participants experiencing PFS (95% CI 195 fewer to 56 fewer) per 1000 participants. Sunitinib probably reduces OS (HR 1.90, 95% CI 1.36 to 2.65; 1 study, 861 participants; moderate-certainty evidence). Based on the control event risk of 880 per 1000 in this trial at 12 months, this would result in 96 fewer OSs (95% CI 167 fewer to 40 fewer) per 1000 participants. Sunitinib may reduce SAEs as compared to pembrolizumab plus axitinib (RR 0.90, 95% CI 0.81 to 1.02; 1 study, 854 participants; low-certainty evidence) although the CI includes the possibility of no effect. Based on the control event risk of 604 per 1000 in this trial, this corresponds to 60 fewer SAEs (95% CI 115 fewer to 12 more) per 1000 participants.  4. Sunitinib versus nivolumab and ipilimumab Sunitinib may reduce PFS as compared to nivolumab plus ipilimumab (HR 1.30, 95% CI 1.11 to 1.52; 1 study, 847 participants; low-certainty evidence). Based on the control event risk of 280 per 1000 in this trial at 30 months' follow-up, this corresponds to 89 fewer PFSs (95% CI 136 fewer to 37 fewer) per 1000 participants. Sunitinib reduces OS (HR 1.52, 95% CI 1.23 to 1.89; 1 study, 847 participants; high-certainty evidence). Based on the control event risk 600 per 1000 in this trial at 30 months, this would result in 140 fewer OSs (95% CI 219 fewer to 67 fewer) per 1000 participants. Sunitinib probably increases SAEs (RR 1.37, 95% CI 1.22 to 1.53; 1 study, 1082 participants; moderate-certainty evidence). Based on the control event risk of 457 per 1000 in this trial, this corresponds to 169 more SAEs (95% CI 101 more to 242 more) per 1000 participants. AUTHORS' CONCLUSIONS: Based on the low to high certainty of evidence, several combinations of immune checkpoint inhibitors appear to be superior to single-agent targeted therapy in terms of PFS and OS, and with a favourable AE profile. Some single-agent targeted therapies demonstrated a similar or improved oncological outcome compared to others; minor differences were observed for AE within this group. The certainty of evidence was variable ranging from high to very low and all comparisons were based on single trials.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Renais/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Adulto , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/efeitos adversos , Antineoplásicos Imunológicos/uso terapêutico , Axitinibe/efeitos adversos , Axitinibe/uso terapêutico , Bevacizumab/efeitos adversos , Bevacizumab/uso terapêutico , Viés , Carcinoma de Células Renais/mortalidade , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Compostos de Fenilureia/efeitos adversos , Compostos de Fenilureia/uso terapêutico , Intervalo Livre de Progressão , Inibidores de Proteínas Quinases/efeitos adversos , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Qualidade de Vida , Quinolinas/efeitos adversos , Quinolinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto , Receptores de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Sirolimo/efeitos adversos , Sirolimo/análogos & derivados , Sirolimo/uso terapêutico , Sorafenibe/efeitos adversos , Sorafenibe/uso terapêutico , Sulfonamidas/efeitos adversos , Sulfonamidas/uso terapêutico , Sunitinibe/efeitos adversos , Sunitinibe/uso terapêutico
3.
Medicine (Baltimore) ; 99(31): e21211, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-32756099

RESUMO

RATIONALE: Within a rapidly expanding therapeutic armamentarium, the combination of everolimus (Eve) plus exemestane (Exe) utility needs to be reinstated in hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) metastatic breast cancer (MBC). PATIENT CONCERNS: We herein report on a patient affected by HR+ HER2- MBC treated with radical surgery after neoadjuvant chemotherapy, who relapsed early on adjuvant tamoxifen, progressed rapidly on first line anastrozole, and failed treatment with third line capecitabine. DIAGNOSES: Metastatic luminal breast cancer progressed under standard endocrine therapy and chemotherapy. INTERVENTIONS: Third line with Eve plus Exe was given after chemotherapy. OUTCOMES: Patient experienced a 5-year progression free interval. LESSONS: Eve plus Exe remains a valid option in HR+HER2- MBC.


Assuntos
Neoplasias da Mama/diagnóstico , Carcinoma Lobular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Androstadienos/administração & dosagem , Androstadienos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/mortalidade , Carcinoma Lobular/patologia , Everolimo/administração & dosagem , Everolimo/uso terapêutico , Feminino , Humanos , Neoplasias Hepáticas/tratamento farmacológico , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Pessoa de Meia-Idade , Pré-Menopausa , Intervalo Livre de Progressão
4.
Gastroenterol Hepatol ; 43(8): 457-463, 2020 Oct.
Artigo em Inglês, Espanhol | MEDLINE | ID: mdl-32646657

RESUMO

SARS-CoV-2 infection has produced a pandemic with serious consequences for our health care system. Although liver transplant patients represent only a minority of the population, the hepatologists who follow these patients have tried to coordinate efforts to produce a protocol the management of immunosuppression during SARS-CoV-2 infection. Although there are no solid studies to support general recommendations, experiences with other viral infections (hepatitis C, cytomegalovirus) suggest that management of immunosuppression without mycophenolate mofetil or m-Tor inhibitors (drugs that are also associated with leukopenia and lymphopenia) may be beneficial. It is also important to pay attention to possible drug interactions, especially in the case of tacrolimus, with some of the treatments with antiviral effect given in the context of COVID 19 (lopinavir/ritonavir, azithromycin). Finally, the immunosuppressive effect of immunomodulating drugs (tocilizumab and similar) administered to patients with severe lung disease should be taken into account. The mechanisms of action of the different immunosuppressive drugs are reviewed in this article, as well as their potential effect on SARS-CoV-2 infection, and suggests guidelines for the management of immunosuppression.


Assuntos
Betacoronavirus , Infecções por Coronavirus/epidemiologia , Imunossupressão/efeitos adversos , Imunossupressores/efeitos adversos , Transplante de Fígado , Pandemias , Pneumonia Viral/epidemiologia , Imunidade Adaptativa , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/fisiologia , Inibidores de Calcineurina/efeitos adversos , Inibidores de Calcineurina/farmacologia , Inibidores de Calcineurina/uso terapêutico , Contraindicações de Medicamentos , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/imunologia , Suscetibilidade a Doenças , Interações Medicamentosas , Everolimo/efeitos adversos , Everolimo/farmacologia , Everolimo/uso terapêutico , Glucocorticoides/efeitos adversos , Glucocorticoides/farmacologia , Glucocorticoides/uso terapêutico , Humanos , Imunidade Inata , Hospedeiro Imunocomprometido , Imunossupressão/métodos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/farmacologia , Ácido Micofenólico/uso terapêutico , Pneumonia Viral/imunologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/prevenção & controle , Sirolimo/efeitos adversos , Sirolimo/farmacologia , Sirolimo/uso terapêutico , Serina-Treonina Quinases TOR/antagonistas & inibidores
5.
PLoS One ; 15(7): e0235673, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32645029

RESUMO

BACKGROUND AND OBJECTIVES: This study sought to compare clinical outcomes between bioresorbable scaffolds (BRS) and durable polymer everolimus-eluting metallic stents (DP-EES) in patients with acute myocardial infarction (AMI) undergoing successful percutaneous coronary intervention (PCI). METHODS: From March 2016 to October 2017, 952 patients with AMI without cardiogenic shock undergoing successful PCI with BRS (n = 136) or DP-EES (n = 816) were enrolled from a multicenter, observational Korea Acute Myocardial Infarction Registry. RESULTS: In the crude population, there was no significant difference in the 1-year rate of device-oriented composite endpoint (DOCE) and device thrombosis between the BRS and DP-EES groups (2.2% vs. 4.8%, hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.13-1.41, p = 0.163; 0.7% vs. 0.5%, HR 1.49, 95% CI 0.16-13.4, p = 0.719, respectively). BRS implantation was opted in younger patients (53.7 vs. 62.6 years, p < 0.001) with low-risk profiles, and intravascular image-guided PCI was more preferred in the BRS group (60.3% vs. 27.2%, p < 0.001). CONCLUSIONS: At 1-year follow-up, no differences in the rate of DOCE and device thrombosis were observed between patients with AMI treated with BRS and those treated with DP-EES. Our data suggest that imaging-guided BRS implantation in young patients with low risk profiles could be a reasonable strategy in the setting of AMI.


Assuntos
Implantes Absorvíveis/efeitos adversos , Stents Farmacológicos/efeitos adversos , Infarto do Miocárdio/cirurgia , Intervenção Coronária Percutânea/efeitos adversos , Doença Aguda/terapia , Adulto , Idoso , Fármacos Cardiovasculares/uso terapêutico , Determinação de Ponto Final , Everolimo/uso terapêutico , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/terapia , Modelos de Riscos Proporcionais , República da Coreia , Trombose/etiologia , Tecidos Suporte/efeitos adversos , Resultado do Tratamento
6.
J Cancer Res Clin Oncol ; 146(11): 3013-3023, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32566979

RESUMO

PURPOSE: Everolimus plus exemestane (EVE/EXE) is a registered treatment option for ER-positive, HER2-negative (ER +/HER2-) metastatic breast cancer (MBC), but resistance mechanisms limit efficacy. We aimed to find markers that might help select patients with a higher chance on benefit from EVE/EXE. METHODS: Immunohistochemistry (IHC) of PTEN, p-AKT(Thr308), p-AKT(Ser473), p-4EBP1, p-p70S6K, p-S6RP(Ser240/244), p-ERK1/2 and p-S6RP (Ser235/236) was performed on primary tumour tissue and on biopsies immediately taken from ER +/HER2- MBC patients before the start of standard EVE/EXE (Eudract 2013-004120-11). Unsupervised hierarchical clustering was executed to create heatmaps to distinguish subgroups of preferentially activated and less-activated PI3K/MAPK proteins. Uni- and multivariate Cox models were used for associations with PFS. RESULTS: Primary tumour tissue from 145 patients was retrieved. Median PFS was 5.4 months. Patients without (neo)adjuvant therapy (p = 0.03) or bone only disease (p = 0.04) had longer PFS on EVE/EXE. In primary tumours, neither single proteins nor PI3K/MAPK-associated heatmap subgroups were significantly associated with PFS. In 21 patients a non-osseous biopsy obtained before dosing was useful for continuous scoring, which demonstrated upregulation of several proteins as compared to readings in corresponding primary tumour tissues. These comparisons revealed that increased expression of p-4EBP1 was significantly associated with worse PFS (multivariate HR 3.69, p = 0.05). CONCLUSIONS: IHC of single proteins or heatmap subgroups of the differentially activated PI3K/MAPK pathways was not able to discriminate patients on EVE/EXE with poor or better PFS. Upregulation of p-4EBP1 in pre-treatment biopsies as compared to levels in primary tumours pointed towards shorter PFS.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/tratamento farmacológico , Resistencia a Medicamentos Antineoplásicos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Androstadienos/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/metabolismo , Everolimo/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Intervalo Livre de Progressão , Transdução de Sinais/fisiologia
7.
Transplant Proc ; 52(6): 1829-1832, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32571711

RESUMO

PURPOSE: Everolimus (EVR) is a derivative of sirolimus with a similar mechanism of action. The safety and efficacy of EVR after pediatric living donor liver transplantation (LDLT) are currently unknown. The purpose of this study was to examine the safety and efficacy of EVR as rescue therapy after pediatric LDLT. METHODS: This study included patients younger than 19 years of age who received EVR after LDLT at our institution. EVR was administered as rescue treatment in addition to tacrolimus. In 21 patients, EVR dose, trough level, outcomes, and adverse effects were assessed. RESULTS: Original diseases of patients consisted of biliary atresia (n = 11), Alagille syndrome (n = 3), fulminant hepatitis (n = 3), hepatoblastoma (n = 2), and other (n = 2). Mean age at transplant was 2.0 years (range 0.6-6.2 years). Mean age at initial EVR administration was 8.0 years (range 0.9-18.9 years). Indications for EVR use were graft fibrosis (n = 8), refractory acute cellular rejection (n = 5), renal sparing (n = 4), hepatoblastoma (n = 2), and chronic rejection (CR) (n = 2). Mean duration of administration was 17.1 months (range 2.1-60.4 months). Mean dose was 0.5 mg/m2 twice daily. Mean EVR trough level was 2.5 ng/mL (range 1.5-5.0 ng/mL). Liver function improved and fibrosis did not progress in all patients with CR. However, 14 patients (67%) experienced adverse effects that required EVR dose reduction or discontinuation. CONCLUSION: EVR is tolerable for pediatric patients after LDLT with dose adjustment. EVR had a certain effect to relieve progression on CR. Further follow-up is required.


Assuntos
Everolimo/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Transplante de Fígado , Adolescente , Criança , Pré-Escolar , Quimioterapia Combinada , Feminino , Humanos , Lactente , Doadores Vivos , Masculino , Complicações Pós-Operatórias/tratamento farmacológico , Tacrolimo/uso terapêutico
8.
Expert Rev Med Devices ; 17(7): 671-682, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32543934

RESUMO

INTRODUCTION: Coronary percutaneous interventions have evolved from plain old balloon angioplasty (POBA) to stent implantation, which itself evolved from bare-metal stents (BMS) to the new biodegradable stents which try to restore endothelial function. Currently, the most commonly used stent is the everolimus-eluting stent. AREAS COVERED: This review will cover the current status of durable polymer everolimus-eluting stent, its history, and future perspectives. Nowadays, the everolimus-eluting stent is the most used device in the acute and chronic settings due to its safety and efficacy. EXPERT OPINION: Durable polymer everolimus-eluting stent, supported by much evidence, has demonstrated its efficacy and safety, not only in de novo artery lesions, but in multiples scenarios, such as the acute setting and diabetic population, becoming one of the most polyvalent stents available. Nowadays, research is focused on the reduction of antiplatelet treatment duration. Similar rates of stent thrombosis with short dual antiplatelet treatment regimens of 1 to 3 months compared to pronged treatment have been observed. However, specific studies should be performed to evaluate this possibility.


Assuntos
Stents Farmacológicos/tendências , Everolimo/uso terapêutico , Polímeros/química , Síndrome Coronariana Aguda/tratamento farmacológico , Stents Farmacológicos/efeitos adversos , Everolimo/efeitos adversos , Everolimo/química , Humanos , Resultado do Tratamento
9.
Expert Rev Med Devices ; 17(5): 383-390, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32274941

RESUMO

Introduction: Coronary angioplasty with the use of stents transformed the percutaneous treatment of coronary artery disease. First-generation drug-eluting stents reduced the risk of restenosis but carried a threat of late stent thrombosis. Second-generation drug-eluting stents resolved these issues and have proven so far very good safety and efficacy performance.Areas covered: This article aims to describe the new XIENCE® Sierra everolimus-eluting coronary stent system, to analyze the available data so far with regards to the safety, the effectiveness, and the overall clinical performance of the device and to seek future perspectives.Expert opinion: XIENCE® Sierra everolimus-eluting coronary stent carries all the positive features of the precursor stents of the XIENCE® family and brings an ultra-low crossing profile which further increases deliverability and flexibility. CoCr-everolimus-eluting stents are among if not the most extensively investigated coronary stents and have demonstrated over the years a consistently remarkable low risk of acute, subacute, late, and very late stent thrombosis and are considered a trustworthy device in the interventional management of complex coronary artery disease.


Assuntos
Doença da Artéria Coronariana/cirurgia , Stents Farmacológicos/efeitos adversos , Equipamentos e Provisões/efeitos adversos , Ensaios Clínicos como Assunto , Everolimo/uso terapêutico , Humanos , Vigilância de Produtos Comercializados , Resultado do Tratamento
11.
J Urol ; 204(3): 531-537, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32250730

RESUMO

PURPOSE: Everolimus decreases tumor volume of renal angiomyolipomas in patients with tuberous sclerosis. No prospective data are available regarding the effect of everolimus on the growth kinetics in patients with sporadic angiomyolipomas. We sought to determine the safety and efficacy of everolimus in the volumetric reduction of sporadic angiomyolipomas. MATERIALS AND METHODS: This multi-institutional, prospective, phase II trial, enrolled patients with 3 cm or larger sporadic angiomyolipomas who were candidates for surgical resection or percutaneous angioembolization. Patients received 10 mg everolimus daily for 4 planned 28-day cycles. Response was defined as a 25% or greater volumetric reduction of patient angiomyolipoma. Baseline, 4, 6 and 12-month volumetric analyses were performed using magnetic resonance imaging. Everolimus was discontinued in those with less than 25% volumetric reduction after 4 cycles. Those with 25% or greater volumetric reduction received 2 additional cycles. The primary outcomes were the efficacy of everolimus in the volumetric reduction of angiomyolipomas by 25% or more, and the safety and tolerability of everolimus. RESULTS: Overall 20 patients were enrolled at 5 centers. Of these patients 11 (55%) completed 4 cycles and 7 (35%) completed 6 cycles. Efficacy was demonstrated, with 10 of 18 (55.6%) patients exhibiting a 25% or greater reduction in tumor volume at 4 months (median 58.5%) and 10 of 14 (71.4%) patients exhibiting a 25% or greater reduction in tumor volume at 6 months (median 58.2%). Four (20%) patients were withdrawn due to protocol defined toxicities and 8 (40%) self-withdrew from the study due to side effects. CONCLUSIONS: Everolimus was effective in causing volumetric reduction of angiomyolipomas by 25% or greater in most patients but was associated with a high rate of treatment discontinuation.


Assuntos
Angiomiolipoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Angiomiolipoma/etiologia , Angiomiolipoma/patologia , Feminino , Humanos , Neoplasias Renais/etiologia , Neoplasias Renais/patologia , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Esclerose Tuberosa/complicações
12.
Transplant Proc ; 52(3): 836-842, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32113691

RESUMO

BACKGROUND: There is little evidence on the long-term effects of calcineurin inhibitor (CNI) withdrawal and substitution with everolimus and mycophenolate mofetil in maintenance therapy of patients who have received heart transplants and have concurrent CNI nephrotoxicity. Aims of this study were to evaluate the progression of renal dysfunction after discontinuation of CNIs and to monitor for major adverse events after therapy change. METHODS: Data from 41 patients who underwent heart transplant and have different degrees of renal dysfunction (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2), without evidence of proteinuria, and in whom CNI therapy was replaced by everolimus, were analyzed. At the time of CNI withdrawal, clinical parameters, echocardiographic data, blood tests of renal function, and monitoring of adverse events were recorded. The median follow-up period was 5 years ± 28 months. RESULTS: In 52% of patients, there was a clear improvement in renal function (10.5 mL/min/1.73 m2 of extra eGFR on average). The former were characterized by less advanced age and a short time from the heart transplant. The echocardiographic parameters showed a significant reduction in septum thickness (11.58 ± 2 mm vs 10.29 ± 2 mm; P = .0001) and in left ventricle posterior wall thickness (10.74 ± 1 mm vs 9.74 ± 1 mm; P = .0004). The incidence of late acute rejection and cardiac allograft vasculopathy was similar in our population compared to literature data. CONCLUSIONS: A therapeutic switch from CNIs to everolimus and mycophenolate mofetil can improve renal function in patients with CNI nephrotoxicity, especially in those with a shorter time period from transplantation, without exposing them to a higher incidence of late acute rejection and cardiac allograft vasculopathy.


Assuntos
Everolimo/uso terapêutico , Transplante de Coração , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Complicações Pós-Operatórias/tratamento farmacológico , Insuficiência Renal/tratamento farmacológico , Adulto , Inibidores de Calcineurina/efeitos adversos , Substituição de Medicamentos , Feminino , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/induzido quimicamente , Insuficiência Renal/induzido quimicamente , Resultado do Tratamento
13.
Medicine (Baltimore) ; 99(13): e19618, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32221087

RESUMO

BACKGROUND: Recently, many endocrine therapies have become available for hormone receptor-positive, human epidermal growth factor receptor 2-negative, pretreated, advanced breast cancer. Direct comparisons of these novel treatments to assess their added value, however, are lacking METHODS:: Our aim was to synthesize available evidence to compare all current endocrine treatments for hormone receptor-positive / human epidermal growth factor receptor 2-negative advanced breast cancer. We performed a systematic review to identify available randomized controlled trial evidence. We searched Embase, MEDLINE, and the Cochrane Central Register of Controlled Clinical Trials. Two trials presented at international oncology congresses (American Society of Clinical Oncology [ASCO]) were added to include the most recent evidence. A frequent network meta-analysis was used, and the surface under cumulative ranking area (SUCRA) was calculated to determine the best treatment RESULTS:: In total, 32 trials and 12,726 patients were identified, including 27 arms. Compared with fulvestrant 500 mg alone, novel target inhibitors combined with fulvestrant or exemestane had significantly prolonged progression-free survival with hazard ratios ranging from 0.62 to 0.82. Fulvestrant 500 mg plus palbociclib 125 mg and exemestane 25 mg plus entinostat 5 mg similarly extended progression-free survival (hazard ratio: 0.64 and 0.62 with SUCRA values of 91% and 92%, respectively). The exemestane 25 mg plus everolimus 10 mg combination had the best clinical benefit rate (risk ratio: 1.84, SUCRA: 91%) and overall response rate (risk ratio: 6.05, SUCRA: 97%) CONCLUSIONS:: On the basis of this analysis, the 2 combinations of exemestane plus everolimus and fulvestrant plus palbociclib were the best treatment options.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pós-Menopausa , Receptor ErbB-2/biossíntese , Androstadienos/uso terapêutico , Antineoplásicos Hormonais/administração & dosagem , Antineoplásicos Hormonais/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzamidas , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Everolimo/uso terapêutico , Feminino , Fulvestranto/uso terapêutico , Humanos , Gradação de Tumores , Metanálise em Rede , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Ensaios Clínicos Controlados Aleatórios como Assunto
14.
Leuk Res ; 91: 106337, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32200189

RESUMO

The tyrosine kinase inhibitors (TKIs) have revolutionized the management of chronic myeloid leukemia (CML) and BCR-ABL1 inhibitors form the mainstay of CML treatment. Although patients with CML generally do well under TKI therapy, there is a subgroup of patients who are resistant and/or intolerant to TKIs. In these group of patients, there is the need of additional treatment strategies. In this review, we provide an update on the current knowledge of these novel treatment approaches that can be used alone and/or in combination with TKIs.


Assuntos
Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Proteínas de Fusão bcr-abl/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Terapia de Alvo Molecular/métodos , Ensaios Clínicos como Assunto , Resistencia a Medicamentos Antineoplásicos/genética , Everolimo/uso terapêutico , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Proteínas de Fusão bcr-abl/imunologia , Expressão Gênica , Inibidores de Histona Desacetilases/uso terapêutico , Mepesuccinato de Omacetaxina/uso terapêutico , Humanos , Imunoterapia/métodos , Interferon-alfa/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Leucemia Mielogênica Crônica BCR-ABL Positiva/imunologia , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Niacinamida/análogos & derivados , Niacinamida/uso terapêutico , Piperidinas/uso terapêutico , Polietilenoglicóis/uso terapêutico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Piridinas/uso terapêutico , Quinolonas/uso terapêutico , Proteínas Recombinantes/uso terapêutico
15.
Biochem Pharmacol ; 175: 113921, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32201213

RESUMO

The mammalian target of rapamycin (mTOR) pathway converges diverse environmental cues to support the lung cancer growth and survival. However, the mTOR-targeted mono-therapy does not achieve expected therapeutic effect. Here, we revealed that fangchinoline (FCL), an active alkaloid that purified from the traditional Chinese medicine Stephania tetrandra S. Moore, enhanced the anti-lung cancer effect of mTOR inhibitor everolimus (EVE). The combination of EVE and FCL was effective to activate Notch 3, and subsequently evoked its downstream target c-MYC. The blockage of Notch 3 signal by the molecular inhibitor of γ-secretase or siRNA of Notch 3 reduced the c-MYC expression and attenuated the combinational efficacy of EVE and FCL on cell apoptosis and proliferation. Moreover, the c-MYC could bind to the C/EBP homologous protein (CHOP) promoter and facilitate CHOP transcription. The conditional genetic deletion of CHOP reduced the apoptosis on lung cancer cells to the same degree as blockage of Notch 3/c-MYC axis, providing further evidence for that the Notch 3/c-MYC axis regulates the transcription of CHOP and finally induces apoptosis upon co-treatment of FCL and EVE in lung cancer cells. Overall, our findings, to the best of our knowledge, firstly link CHOP to Notch 3/c-MYC axis-dependent apoptosis and provide the Notch 3/c-MYC/CHOP activation as a promising strategy for mTOR-targeted combination therapy in lung cancer treatment.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Everolimo/farmacologia , Neoplasias Pulmonares/metabolismo , Receptor Notch3/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Fator de Transcrição CHOP/metabolismo , Fatores de Transcrição/metabolismo , Células A549 , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/fisiologia , Everolimo/uso terapêutico , Células HEK293 , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores
16.
Transplant Proc ; 52(5): 1376-1379, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32213293

RESUMO

BACKGROUND: Pancreas transplant is an effective treatment for insulin-dependent diabetic individuals with end-stage renal disease, yet immunosuppression-associated adverse events may adversely affect patient and graft survival. The aim of the study was to document whether mammalian target of rapamycin inhibitors (mTORi) are safe and effective as a second-line drug after pancreas transplant. METHODOLOGY: An observational single-center study was performed in a cohort of 490 simultaneous pancreas-kidney transplant and 45 pancreas-after-kidney transplant individuals after conversion to mTORi (n = 13) owing to adverse events of either tacrolimus or mycophenolate. RESULTS: mTORi conversion was performed 11.5 ± 10.1 (range, 1-28) months after pancreas transplant, mainly owing to cytomegalovirus infection and gastrointestinal intolerance. We frequently observed clinical complications after mTORi conversion, yet creatinine, eGFR, proteinuria, fasting plasma glucose, HbA1c, and C-peptide remained stable throughout the study (mean follow-up 8.2 ± 5, range 1-17) years, as did the lipid profile (P > .05). However, graft loss occurred in almost 20% of patients owing to chronic alterations. LIMITATIONS: The small number of patients and a single-center cohort were limitations of the study. CONCLUSIONS: Late mTORi conversion is a safe and effective approach when tacrolimus or mycophenolate-mediated adverse events occur after pancreas transplant.


Assuntos
Everolimo/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Pâncreas/métodos , Sirolimo/uso terapêutico , Adulto , Substituição de Medicamentos/métodos , Feminino , Rejeição de Enxerto/prevenção & controle , Sobrevivência de Enxerto/efeitos dos fármacos , Humanos , Imunossupressão/métodos , Transplante de Rim , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
17.
Dtsch Med Wochenschr ; 145(3): 189-194, 2020 02.
Artigo em Alemão | MEDLINE | ID: mdl-32018295

RESUMO

HISTORY: A 72-year-old heart transplant recipient presented to the hospital with progressive dyspnea. His immunosuppressive therapy was switched to the mTOR-inhibitor everolimus. A few months before, due to a progressive decline in renal function. Primarily, a community-acquired pneumonia was suspected and an empiric antibiotic therapy was initiated. Despite antimicrobial treatment, an acute respiratory distress syndrome developed and mechanical ventilation became necessary. INVESTIGATIONS: During the following extensive diagnostic a transbronchial lung biopsy was performed and histological analysis revealed a drug induced lung injury. DIAGNOSIS: Based on the clinical and histological findings an everolimus induced pneumonitis was suspected. TREATMENT AND COURSE: The drug was immediately discontinued and a high-dose steroid treatment was started, resulting in a significant improvement of respiratory function. CONCLUSION: Everolimus-related interstitial pneumonitis represents a rare but important adverse effect of everolimus in immunosuppressed patients. Recognition of everolimus induced pneumonitis is of high clinical relevance and should be considered in all patients on everolimus presenting with respiratory symptoms of unknown origin.


Assuntos
Transplante de Coração , Imunossupressores , Pneumonia/induzido quimicamente , Complicações Pós-Operatórias/induzido quimicamente , Serina-Treonina Quinases TOR/antagonistas & inibidores , Idoso , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Everolimo/uso terapêutico , Evolução Fatal , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Pulmão/diagnóstico por imagem , Pulmão/patologia , Masculino , Pneumonia/diagnóstico por imagem , Pneumonia/patologia
18.
Asia Pac J Clin Oncol ; 16(3): 150-157, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32030887

RESUMO

AIMS: This multicenter phase II trial evaluates the efficacy of everolimus in poor prognosis grade 2 (G2) pancreatic neuroendocrine tumors (PNETs), defined by 2-[fluorine-18]fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography (PET) avidity. FDG-PET avidity in NETs is associated with a significantly higher risk of death, outperforming Ki-67 index or liver metastases as a poor prognostic factor. We hypothesized that everolimus has efficacy in patients with FDG-PET-avid G2 PNETs and prospectively evaluated progression-free survival (PFS) and response in the first-line setting. METHODS: Patients with FDG-PET-avid G2 advanced PNET received everolimus 10 mg daily until disease progression. Patients were staged every 12 weeks with CT/MRI and FDG-PET and every 24 weeks with Gallium 68 (68Ga) 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-octreotate (DOTATATE, GaTate) PET. The primary endpoint was PFS at 6 months. Overall survival rate, PET/structural imaging response and toxicity were also measured. RESULTS: Nine patients were accrued from December 2012 to February 2015. Median treatment duration was 13.8 months. The estimated PFS rate at 6 months was 78%. The best response on CT/MRI was stable disease in nine patients (100%) and partial response on FDG-PET in five patients (55.5%). Treatment-related adverse effects were consistent with previous studies of everolimus. CONCLUSION: Everolimus is active with prolonged disease control in poor prognosis FDG-avid G2 PNETs. Treatment individualization based on functional imaging warrants further evaluation.


Assuntos
Everolimo/uso terapêutico , Fluordesoxiglucose F18/uso terapêutico , Tumores Neuroendócrinos/diagnóstico por imagem , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/uso terapêutico , Adulto , Idoso , Everolimo/farmacologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Taxa de Sobrevida
19.
Transplant Proc ; 52(2): 622-624, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035672

RESUMO

Kaposi sarcoma (KS) is the most common tumor in patients with human immunodeficiency virus (HIV), and its frequency is increasing after organ transplantation in HIV-negative patients. A 28-year-old woman had preemptive kidney transplantation from her 48-year-old mother. In the postoperative ninth month, an exophytic mass was found in the upper medial conjunctiva of the right eye. The lesion was excised under local anesthesia, and cryotherapy was applied to the surgical area. The biopsy result was reported as KS. Treatment with tacrolimus was switched to everolimus (EVO), but EVO was discontinued because of pneumonitis. The patient was followed without any recurrences after the excision of the conjunctival lesion. No local or systemic recurrence was observed in the 14th month after surgical excision and local cryotherapy. Local treatment and the reduction of immunosuppressive therapy may be effective in the treatment of conjunctival KS.


Assuntos
Neoplasias da Túnica Conjuntiva/imunologia , Neoplasias da Túnica Conjuntiva/cirurgia , Hospedeiro Imunocomprometido , Transplante de Rim , Sarcoma de Kaposi/imunologia , Sarcoma de Kaposi/cirurgia , Adulto , Everolimo/uso terapêutico , Feminino , Infecções por HIV/complicações , Humanos , Imunossupressão/efeitos adversos , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Tacrolimo/uso terapêutico
20.
Transplant Proc ; 52(2): 553-555, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32035682

RESUMO

BACKGROUND: Calcineurin inhibitors are associated with the development of de novo tumors and increased recurrence of hepatocellular carcinoma after liver transplant. It has been suggested that mammalian target of rapamycin inhibitors (everolimus [EVR]) may improve prognosis. We analyzed our experience on the use of EVR in malignant neoplasms in liver transplantation. METHODS: We performed a retrospective descriptive analysis of 477 transplants performed between 2002 and 2019 at Virgen de las Nieves Hospital. A total of 100 patients received EVR; 23 transplants were because of tumor disease (23%), with de novo tumor in 12 patients and hepatocarcinoma in 11. The statistical study was carried out using the statistical program SPSS 17.0 software. RESULTS: The study included 18 male patients (78.3%) and 5 female patients (21.7%) with an average age of 59.67 years. The most common indications of liver transplant have been alcoholic cirrhosis in 39% and hepatitis C virus cirrhosis in 21.7%. De novo tumors were lung neoplasm in 4 patients (33.3%), lymphoma in 2 patients(16.7%), oropharynx in 2 patients (16.7%), skin tumors in 2 patients (16.7%), and a kidney tumor (8.3%) in 1 patient. As for hepatocellular carcinoma, 8 patients met Milan criteria on the explant (61.5%). Tacrolimus was discontinued in all cases. The average onset time of post-transplant EVR was 2231.42 days in the de novo neoplasms and 307.45 days in those receiving transplants because of hepatocellular carcinoma (P = .05). We observed 5 deaths (21.7%). CONCLUSION: Although the beneficial long-term role of EVR in liver transplant recipients with tumor disease is not demonstrated, it is used by most transplant units, both in de novo neoplasms and those receiving transplants because of hepatocellular carcinoma.


Assuntos
Antineoplásicos/uso terapêutico , Carcinoma Hepatocelular/terapia , Everolimo/uso terapêutico , Neoplasias Hepáticas/terapia , Recidiva Local de Neoplasia/tratamento farmacológico , Complicações Pós-Operatórias/tratamento farmacológico , Adulto , Inibidores de Calcineurina/efeitos adversos , Carcinoma Hepatocelular/patologia , Feminino , Humanos , Neoplasias Hepáticas/patologia , Transplante de Fígado/efeitos adversos , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/etiologia , Complicações Pós-Operatórias/etiologia , Estudos Retrospectivos , Resultado do Tratamento
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