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1.
BMJ Open ; 11(10): e052138, 2021 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-34620664

RESUMO

OBJECTIVES: Development of pharmaceutical agents in transplantation is currently limited by long waits for hard endpoints. We applied a validated integrative risk-prognostication system integrative Box (iBox) as a surrogate endpoint to the TRANSFORM Study, a large randomised controlled trial, to project individual patient long-term kidney allograft survival from 1 year to 11 years after randomisation. DESIGN: Post-hoc analysis of a randomised open-label controlled trial. SETTING: Multicentre study including 186 centres in 42 countries worldwide. PARTICIPANTS: 2037 de novo kidney transplant recipients. INTERVENTION: Participants were randomised (1:1) to receive everolimus with reduced-exposure calcineurin inhibitor (EVR+rCNI) or mycophenolic acid with standard-exposure CNI (MPA+sCNI). PRIMARY OUTCOME MEASURE: The iBox scores were computed for each participant at 1 year after randomisation using functional, immunological and histological parameters. Individual long-term death-censored allograft survival over 4, 6 and 11 years after randomisation was projected with the iBox risk-prognostication system. RESULTS: Overall, 940 patients receiving EVR+rCNI and 932 receiving MPA+sCNI completed the 1-year visit. iBox scores generated at 1 year yielded graft survival prediction rates of 90.9% vs 92.1%, 87.9% vs 89.5%, and 80.0% vs 82.4% in the EVR+rCNI versus MPA+sCNI arms at 4, 6, and 11 years post-randomisation, respectively (all differences below the 10% non-inferiority margin defined by study protocol). Inclusion of immunological and histological Banff diagnoses parameters in iBox scores resulted in comparable and non-inferior predicted graft survival for both treatments. CONCLUSIONS: This proof-of-concept study provides the first application of a validated prognostication system as a surrogate endpoint in the field of transplantation. The iBox system, by projecting kidney allograft survival up to 11 years post-randomisation, confirms the non-inferiority of EVR+rCNI versus MPA+sCNI regimen. Given the current process engaged for surrogate endpoints qualification, this study illustrates the potential to fast track development of pharmaceutical agents. TRIAL REGISTRATION NUMBER: TRANSFORM trial: NCT01950819.iBox prognostication system: NCT03474003.


Assuntos
Transplante de Rim , Biomarcadores , Inibidores de Calcineurina , Everolimo , Humanos , Ácido Micofenólico/uso terapêutico
2.
Cancer Invest ; 39(10): 871-879, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34643126

RESUMO

Novel therapeutics are needed for patients with relapsed or refractory diffuse large B-cell lymphoma (R/R DLBCL). Everolimus is an mTOR pathway inhibitor with synergistic anti-tumor activity when combined with histone deacetylase inhibitors, such as panobinostat, in preclinical lymphoma models. In this Phase II study, we evaluated overall response rate to single and combination everolimus and panobinostat in R/R DLBCL. Fifteen patients were enrolled to single-agent and 18 to combination. One patient responded to everolimus, while none responded to panobinostat. Though 25% of patients responded to combination therapy, responses were not durable with significant toxicity. We demonstrated minimal single-agent activity and prohibitive toxicity with combination therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Everolimo/uso terapêutico , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Panobinostat/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Panobinostat/administração & dosagem , Panobinostat/efeitos adversos , Estudos Prospectivos , Recidiva
4.
J Invasive Cardiol ; 33(10): E784-E790, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34609325

RESUMO

BACKGROUND: Outcomes from the new Synergy Megatron drug-eluting stent (DES) platform (Boston Scientific) are not yet reported. This study sought to evaluate periprocedural outcomes in patients undergoing percutaneous coronary intervention (PCI) using this technology. METHODS: This was a retrospective study across two United Kingdom centers of 139 patients undergoing PCI of 146 coronary lesions using the Synergy Megatron DES. The primary endpoint was the rate of cardiovascular death. The secondary endpoint was the rate of a composite of non-fatal myocardial infarction, target-vessel revascularization, in-stent restenosis, and probable/definite stent thrombosis. Available intravascular ultrasound (IVUS) imaging was reviewed post hoc and evaluated according to predefined IVUS optimization criteria. RESULTS: Mean follow-up duration was 137.3 ± 38.3 days. The primary endpoint occurred in 0.7% of patients and the secondary endpoint occurred in 0.0% of patients. There were no cases of longitudinal stent deformation (LSD); in patients undergoing an IVUS-guided procedure, our criteria for successful IVUS optimization was achieved in 74.1% of left main stem (LMS) and 83.3% of right coronary artery (RCA) lesions. Mean minimal stent area (MSA) was 14.5 ± 3.4 mm² in the LMS, 10.0 ± 2.5 mm² in the left anterior descending coronary artery, 9.8 ± 3.0 mm² in the left circumflex, and 12.2 ± 4.0 mm² in the RCA. CONCLUSION: This study demonstrated very low rates of short-term major adverse cardiovascular events with no cases of LSD or acute/subacute stent thrombosis. It highlights the overexpansion capabilities of the Synergy Megatron DES platform. The technology safely and effectively facilitates IVUS-optimized stent parameters for the treatment of large proximal vessels and bifurcations.


Assuntos
Doença da Artéria Coronariana , Stents Farmacológicos , Intervenção Coronária Percutânea , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/cirurgia , Everolimo/farmacologia , Humanos , Estudos Retrospectivos , Stents , Resultado do Tratamento , Ultrassonografia de Intervenção
5.
Clin Adv Hematol Oncol ; 19(9): 582-593, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34495022

RESUMO

Neuroendocrine tumors (NETs) are a heterogeneous group of epithelial neoplasms with predominantly neural and endocrine differentiation that have the ability to produce peptide hormones and other biologically active substances. The histologic characterization of NETs based on differentiation and grading is crucial to determining prognosis and treatment. Surgery still offers the best chance of cure for patients with NETs, and tumor resection is the preferred approach when possible. For locally advanced or metastatic disease, approaches to treatment can vary widely depending on the extent of disease and goals of therapy. A better understanding of the biology of NETs acquired over the last decade has facilitated the development of targeted therapies, such as everolimus and a variety of tyrosine kinase inhibitors. Furthermore, the field of theranostics has led to dramatic improvements in our diagnostic and treatment abilities. Chemotherapy has a role in the treatment of NETs, evidenced by the benefit shown with the combination of temozolomide and capecitabine to treat pancreatic NETs. Somatostatin analogues are a mainstay of treatment because they reduce secretory products and have antiproliferative effects on NET cells. In this work, we aim to review the landscape for the diagnosis and treatment of well-differentiated NETs.


Assuntos
Antineoplásicos , Tumores Neuroendócrinos , Antineoplásicos/uso terapêutico , Capecitabina/uso terapêutico , Everolimo/uso terapêutico , Humanos , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas , Somatostatina/uso terapêutico
6.
JACC Cardiovasc Interv ; 14(17): 1870-1883, 2021 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-34503737

RESUMO

OBJECTIVES: The aim of this study was to evaluate 2 abbreviated dual-antiplatelet therapy (DAPT) regimens in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI). BACKGROUND: Current-generation drug-eluting stents are preferred over bare-metal stents for HBR patients, but their optimal DAPT management remains unknown. METHODS: The XIENCE Short DAPT program included 3 prospective, multicenter, single-arm studies enrolling HBR patients who underwent successful PCI with a cobalt-chromium everolimus-eluting stent. After 1 month (XIENCE 28 USA and XIENCE 28 Global) or 3 months (XIENCE 90) of DAPT, event-free patients discontinued the P2Y12 inhibitor. The postmarketing approval XIENCE V USA study was used as historical control in a propensity score-stratified analysis. RESULTS: A total of 3,652 patients were enrolled. The propensity-adjusted rate of the primary endpoint of all-cause mortality or myocardial infarction was 5.4% among 1,693 patients on 3-month DAPT versus 5.4% in the 12-month DAPT historical control (Pnoninferiority = 0.0063) and 3.5% among 1,392 patients on 1-month DAPT versus 4.3% in the 6-month DAPT historical control (Pnoninferiority = 0.0005). Bleeding Academic Research Consortium (BARC) types 2 to 5 bleeding was not significantly lower with 3- or 1-month DAPT, while BARC types 3 to 5 bleeding was reduced in both experimental groups. The rate of definite or probable stent thrombosis was 0.2% in XIENCE 90 (P < 0.0001 for the performance goal of 1.2%) and 0.3% in XIENCE 28. CONCLUSIONS: Among HBR patients undergoing PCI with cobalt-chromium everolimus-eluting stents, DAPT for 1 or 3 months was noninferior to 6 or 12 months of DAPT for ischemic outcomes and may be associated with less major bleeding and a low incidence of stent thrombosis.


Assuntos
Stents Farmacológicos , Intervenção Coronária Percutânea , Quimioterapia Combinada , Everolimo/efeitos adversos , Hemorragia/induzido quimicamente , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Inibidores da Agregação Plaquetária/efeitos adversos , Estudos Prospectivos , Resultado do Tratamento
7.
Ann Transplant ; 26: e932434, 2021 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-34531361

RESUMO

BACKGROUND Calcineurin inhibitor drugs (CNI), which are the basis of immunosuppression in kidney transplantation, contribute to renal graft loss, with increased morbidity and mortality due to their potentially harmful effects on the renal graft, cardiovascular system, and tumor pathology. For this reason, the mammalian target of rapamycin inhibitors (mTORi) such as sirolimus (SRL) and everolimus (EVE) has been preferred more frequently, as they are associated with fewer complications and longer graft function. MATERIAL AND METHODS We enrolled 89 adult renal transplant patients (37 patients on mTORi and 52 on CNI) who had similar age, sex, primary renal disease, dialysis type, post-transplant follow-up period, and donor type. We analyzed and compared the data between patients using mTORi for longer than 5 years and those using CNI regarding pre- and post-transplant panel reactive antibody (PRA), and donor-specific antibody (DSA), as well as post-transplantation and current graft functions. RESULTS Although those using mTORi for more than 5 years had significantly higher mismatch rates (P=0.024) than those using CNI, there was no significant change in PRA and DSA levels. Transplant time was longer in mTORi users (P=0.025). The switch time to mTORi in patients ranged from 0 to 19 years, but the average was 4 years. As expected, actual spot urine protein/creatinine was significantly higher in those using mTORi (P=0.009). Diabetes mellitus (DM) and BK virus nephropathy (BKVN) rates were significantly higher due to switching the regimen from CNI to mTORi. CONCLUSIONS Long-term use of mTORi does not appear to be an immunological problem.


Assuntos
Imunossupressores , Transplante de Rim , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adulto , Inibidores de Calcineurina/efeitos adversos , Everolimo , Feminino , Rejeição de Enxerto/prevenção & controle , Humanos , Imunossupressores/efeitos adversos , Imunossupressores/uso terapêutico , Masculino , Pessoa de Meia-Idade , Sirolimo
8.
BMJ Open ; 11(9): e048190, 2021 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-34561260

RESUMO

OBJECTIVE: To summarise the available evidence on frequency of ovarian cyst development during mammalian target of rapamycin inhibitors (mTORi) treatment. METHODS: PubMed/Medline and EMBASE databases were searched, from 1990 up to March 2020, using the following keywords: 'tacrolimus', 'sirolimus', 'temsirolimus', 'everolimus', 'deforolimus', 'mTOR' and 'ovarian cysts' (Limit: Human, English, full article). Studies were selected for the review if they met the following criteria: clinical studies, studies reporting original data, studies reporting the number of patients using mTORi, studies reporting the number of patients with ovarian cysts.We selected 7 of 20 retrieved studies. Study design, population, sample size, criteria for diagnosis of ovarian cysts, drug doses and follow-up length were extracted. Pooled estimate of incidence was calculated for ovarian cysts as a percentage, with 95% CI. RESULTS: Four hundred-six women were included in the selected studies. The pooled incidence was 37.0% (95% CI 16.0% to 58.1%) for all ovarian cysts, and 17.3% (95% CI 5.6% to 29.1%) for clinically significant ovarian cysts. Based on two articles, comparing mTORi and non-mTORi for immunosuppression, pooled OR for ovarian cyst incidence was 4.62 (95% CI 2.58 to 8.28). CONCLUSION: Ovarian cyst development is a common adverse event during immunosuppression treatment with mTORi. These cysts are benign conditions, but they require pelvic ultrasound follow-up and in some cases hospital admission and surgery.


Assuntos
Cistos Ovarianos , Everolimo , Feminino , Humanos , Incidência , Cistos Ovarianos/induzido quimicamente , Cistos Ovarianos/epidemiologia , Pelve , Serina-Treonina Quinases TOR
9.
Int J Cardiovasc Imaging ; 37(10): 2815-2826, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34420177

RESUMO

PURPOSE: Data regarding vessel healing by optical coherence tomography (OCT) after everolimus-eluting bioresorbable scaffolds (BRS) or everolimus-eluting metallic stent (EES) implantation in acute myocardial infarction (AMI) patients is scarce. We compared OCT findings after BRS or EES implantation in patients with AMI enrolled in a randomized trial. METHODS: In ISAR-Absorb MI, AMI patients were randomized to BRS or EES implantation, with 6-8 month angiographic follow-up. This analysis includes patients who underwent OCT during surveillance angiography. Tissue characterization was done using grey-scale signal intensity analysis. The association between OCT findings and target lesion failure (TLF) at 2 years was investigated. RESULTS: OCT was analyzed in 103 patients (2237 frames, 19,827 struts) at a median of 216 days post-implantation. Of these, 70 were treated with BRS versus 32 with EES. Pre-(92.8 vs. 68.7%, p = 0.002) and post-dilation (51.4 vs. 12.5%, p < 0.001) were more common in BRS as compared to EES. Strut coverage was higher in BRS vs. EES (97.5% vs. 90.9%, p < 0.001). Mean neointimal thickness was comparable in both groups [85.5 (61.9, 124.1) vs. 69.5 (32.7, 127.5) µm, respectively, p = 0.20]. Mature neointimal regions were numerically more common in BRS (43.0% vs. 24.6%; p = 0.35); this difference was statistically significant in ST-elevation myocardial infarction patients (40.9% vs. 21.1%, p = 0.03). At two-years, 8 (7.8%) patients experienced TLF. Mean neointimal area [0.61 (0.21, 1.33) vs. 0.41 (0.11, 0.75) mm2, p = 0.03] and mean neointimal coverage [106.1 (65.2, 214.8) vs. 80.5 (53.5, 122.1) µm, p < 0.01] were higher, with comparable tissue maturity, in lesions with versus without TLF. CONCLUSIONS: In selected patients who underwent OCT surveillance 6-8 months after coronary intervention for AMI with differing implantation characteristics depending on the device type used, vessel healing was more advanced in BRS compared with EES, particularly in the STEMI subgroup.


Assuntos
Stents Farmacológicos , Intervenção Coronária Percutânea , Implantes Absorvíveis , Angiografia Coronária , Everolimo/efeitos adversos , Humanos , Intervenção Coronária Percutânea/efeitos adversos , Valor Preditivo dos Testes , Stents , Tomografia de Coerência Óptica , Resultado do Tratamento
11.
Cells ; 10(7)2021 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-34359829

RESUMO

Breast cancer is the most frequent type of cancer and the major cause of mortality in women. The rapid development of various therapeutic options has led to the improvement of treatment outcomes; nevertheless, one-third of estrogen receptor (ER)-positive patients relapse due to cancer cell acquired resistance. Here, we use dynamic BH3 profiling (DBP), a functional predictive assay that measures net changes in apoptotic priming, to find new effective treatments for ER+ breast cancer. We observed anti-apoptotic adaptations upon treatment that pointed to metronomic therapeutic combinations to enhance cytotoxicity and avoid resistance. Indeed, we found that the anti-apoptotic proteins BCL-xL and MCL-1 are crucial for ER+ breast cancer cells resistance to therapy, as they exert a dual inhibition of the pro-apoptotic protein BIM and compensate for each other. In addition, we identified the AKT inhibitor ipatasertib and two BH3 mimetics targeting these anti-apoptotic proteins, S63845 and A-1331852, as new potential therapies for this type of cancer. Therefore, we postulate the sequential inhibition of both proteins using BH3 mimetics as a new treatment option for refractory and relapsed ER+ breast cancer tumors.


Assuntos
Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Receptor alfa de Estrogênio/genética , Piperazinas/farmacologia , Pirimidinas/farmacologia , Sulfonamidas/farmacologia , Tiofenos/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica , Apoptose/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Sinergismo Farmacológico , Receptor alfa de Estrogênio/metabolismo , Everolimo/farmacologia , Feminino , Fulvestranto/farmacologia , Regulação Neoplásica da Expressão Gênica , Humanos , Células MCF-7 , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/genética , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piridinas/farmacologia , Transdução de Sinais , Tiazóis/farmacologia , Proteína bcl-X/antagonistas & inibidores , Proteína bcl-X/genética , Proteína bcl-X/metabolismo
12.
BMC Cancer ; 21(1): 904, 2021 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-34364385

RESUMO

BACKGROUND: In the phase 3 METEOR trial, cabozantinib improved progression-free survival (PFS) and overall survival (OS) versus everolimus in patients with advanced RCC after prior antiangiogenic therapy. METHODS: In this exploratory analysis, plasma biomarkers from baseline and week 4 from 621 of 658 randomized patients were analyzed for CA9, HGF, MET, GAS6, AXL, VEGF, VEGFR2, and IL-8. PFS and OS were analyzed by baseline biomarker levels as both dichotomized and continuous variables using univariate and multivariable methods. For on-treatment changes, PFS and OS were analyzed using fold change in biomarker levels at week 4. Biomarkers were considered prognostic if p < 0.05 and predictive if pinteraction < 0.05 for the interaction between treatment and biomarker. RESULTS: Hazard ratios for PFS and OS favored cabozantinib versus everolimus for both low and high baseline levels of all biomarkers (hazard ratios ≤0.78). In univariate analyses, low baseline HGF, AXL, and VEGF were prognostic for improvements in both PFS and OS with cabozantinib, and low HGF was prognostic for improvements in both PFS and OS with everolimus. Low AXL was predictive of relative improvement in PFS for cabozantinib versus everolimus. Results were generally consistent when baseline biomarkers were expressed as continuous variables, although none were predictive of benefit with treatment. In multivariable analysis, low baseline HGF was independently prognostic for improved PFS for both cabozantinib and everolimus; low HGF, GAS6, and VEGF were independently prognostic for improved OS with cabozantinib. No biomarkers were independently prognostic for OS with everolimus. On-treatment increases in some biomarkers appeared prognostic for PFS or OS with cabozantinib in univariate analyses; however, none were independently prognostic in multivariable analysis. CONCLUSIONS: PFS and OS were improved with cabozantinib versus everolimus at high and low baseline levels of all biomarkers. Low baseline HGF was consistently identified as a prognostic biomarker for improved PFS or OS with cabozantinib or everolimus, supporting further prospective evaluation of the prognostic significance of HGF in advanced RCC. TRIAL REGISTRATION: ClinicalTrials.gov NCT01865747 (registered on 05/31/2013).


Assuntos
Anilidas/uso terapêutico , Biomarcadores Tumorais/sangue , Carcinoma de Células Renais/sangue , Carcinoma de Células Renais/tratamento farmacológico , Everolimo/uso terapêutico , Neoplasias Renais/sangue , Neoplasias Renais/tratamento farmacológico , Piridinas/uso terapêutico , Anilidas/administração & dosagem , Anilidas/efeitos adversos , Carcinoma de Células Renais/diagnóstico , Carcinoma de Células Renais/mortalidade , Everolimo/administração & dosagem , Everolimo/efeitos adversos , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/diagnóstico , Neoplasias Renais/mortalidade , Prognóstico , Piridinas/administração & dosagem , Piridinas/efeitos adversos , Retratamento , Resultado do Tratamento
13.
Eur J Pharm Sci ; 165: 105926, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34242751

RESUMO

The circadian timing system controls many biological functions in mammals including drug metabolism and detoxification, cell cycle events, and thus may affect pharmacokinetics, target organ toxicity and efficacy of medicines. Selective mTOR (mammalian target of rapamycin) inhibitor everolimus is an immunosuppressant and anticancer drug that is effective against several cancers. The aim of this study was to investigate dosing-time dependent testicular toxicity of subacute everolimus administration in mice. C57BL/6 J male mice were synchronized with Light-Dark (12h:12 h) cycle, with Light-onset at Zeitgeber Time (ZT)-0. Everolimus (5 mg/kg/day) was administered orally to mice at ZT1rest-span or ZT13activity-span for 4 weeks. Body weight loss, clinical signs, changes in testicular weights, testis histology, spermatogenesis and proliferative activity of germinal epithelium of seminiferous tubules were examined. Steady-state everolimus concentrations in testes were determined with validated HPLC method. Everolimus toxicity was less severe following dosing at ZT13 compared to ZT1, as shown with least body weight loss (p<0.001), least reductions in testes weights (p<0.001) and least histopathological findings. Everolimus-induced histological changes on testes included vacuolisation and atrophy of germinal epithelium, and loss of germinal cell attachment. The severity of everolimus-induced histological toxicity on testes was significantly more evident in mice treated at ZT1 than ZT13 (p<0.001). Spermatogenic cell population significantly decreased when everolimus administered at ZT1 compared to ZT13 (p<0.001). Proliferative activity of germinal epithelium was significantly decreased due to treatment at ZT1 compared to ZT13 (p<0.001). Everolimus concentrations in testes indicated a pronounced circadian variation, which was greater in mice treated at ZT1 compared to ZT13 (p<0.05). Our study revealed dosing-time dependent testicular toxicity of everolimus in mice, which was greater in severity when everolimus administered at early rest-span (daytime-ZT1) than early activity-span (nighttime-ZT13). These findings support the concept of everolimus chronotherapy for minimizing reproductive toxicity and increasing the tolerability of everolimus, as a clinical advantage.


Assuntos
Antineoplásicos , Everolimo , Animais , Antineoplásicos/farmacologia , Ritmo Circadiano , Everolimo/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testículo
14.
Clin Mol Hepatol ; 27(4): 589-602, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34293849

RESUMO

BACKGROUND/AIMS: This study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC). METHODS: The data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated. RESULTS: The EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P<0.001) and OS (P<0.001). In multivariable analysis, EVR was identified as an independent prognostic factor for TTR (hazard ratio [HR], 0.248; P=0.001) and OS (HR, 0.145; P<0.001). CONCLUSION: Combined with CNIs, EVR has the potential to prolong long-term survival in patients undergoing LT for HCC. These findings warrant further investigation in a well-designed prospective study.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Transplante de Fígado , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/tratamento farmacológico , Everolimo/uso terapêutico , Humanos , Imunossupressores/uso terapêutico , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/tratamento farmacológico , Recidiva Local de Neoplasia , Estudos Prospectivos , Estudos Retrospectivos
16.
Clin Endocrinol (Oxf) ; 95(5): 744-751, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34323309

RESUMO

PURPOSE: Neuroendocrine neoplasia (NEN) of the thymus is a very rare entity with a poor prognosis. None of the treatments was proofed by studies. Usually, therapy protocols for bronchopulmonary carcinoids are used. So far no data exist on the effect of mammalian target of rapamycin (mTOR) inhibitors. We describe our long-term experience with everolimus and give a thorough review of the therapeutic strategies used so far. PATIENTS AND METHODS: Four patients (mean age 46 years, range 37-55) with progressing thymic NEN (t-NEN) (two well-differentiated atypical carcinoids and two atypical carcinoids with large cell characteristics) were treated with everolimus 10 mg/day after the failure of at least one previous medical therapy. Everolimus was applied after a mean interval of 32.4 months (range 5-56) after the first diagnosis. The follow-up included clinical examination, imaging and chromogranin A testing in 3 or 6 monthly intervals. RESULTS: We observed stable disease for a mean of 20.8 months. Both patients with large cell characteristics t-NEN (Ki-67 of 20%) had rapid progress after 7 and 10 months and had more previous therapies (three and six) than the patients with well-differentiated t-NEN (Ki-67 5% and 10%, progress after 24 and 42 months, one and two previous therapies). No severe side effects occurred. In three of four patients, everolimus led to stable disease for the longest compared to the other nonsurgical therapies used. CONCLUSION: Comparing the sparse data available everolimus is a promising treatment for t-NEN at least in second-line therapy. A low Ki-67 index was associated with a better outcome.


Assuntos
Tumor Carcinoide , Tumores Neuroendócrinos , Adulto , Tumor Carcinoide/tratamento farmacológico , Cromogranina A , Everolimo/uso terapêutico , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Tumores Neuroendócrinos/tratamento farmacológico
17.
BMC Cancer ; 21(1): 862, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34315439

RESUMO

BACKGROUND: Here we evaluated the feasibility, efficacy, tolerability, and treatment-mediated immune modulation of neoadjuvant everolimus plus letrozole versus chemotherapy in treating postmenopausal patients with ER-positive, HER2-negative breast cancer. METHODS: Postmenopausal women with ER-positive, HER2-negative breast cancer who had a primary tumor > 2 cm or positive axillary lymph node(s) proofed by biopsy were randomly (1,1) enrolled to receive neoadjuvant everolimus plus letrozole for 18 weeks or fluorouracil, epirubicin plus cyclophosphamide (FEC) for 6 cycles before surgery. Primary outcome was feasibility of the trial. Secondary outcome included ultrasound response rate, pathological complete response rate, breast-conserving surgery rate, toxicities, treatment-mediated immune modulation and biomarkers. RESULTS: Forty patients were randomized. Completion rate was 90.0% in the neoadjuvant endocrine therapy (NET) arm but 70.0% in the neoadjuvant chemotherapy (NAC) arm. The ultrasound response rate was 65.0% in NET arm and 40.0% in FEC arm, respectively. In terms of the adverse events, clearly favored NET arm. Everolimus plus letrozole increased the ratio of peripheral Tregs to CD4+ T cells and tumor PD-L1 expression, and decreased Ki67 index and tumor-infiltrating Tregs, and patients with a greater increase of tumor-specific CTLs showed more sensitive to NET. CONCLUSION: This pilot trial showed that neoadjuvant everolimus plus letrozole might achieve a favorable ultrasound response rate with low toxicities in treating postmenopausal ER-positive, HER2-negative breast cancer patients. Everolimus plus letrozole might have positive antitumoral immunity effects. Further large randomized controlled trials are needed to confirm our findings. TRAIL REGISTRATION: A Trial of Neoadjuvant Everolimus Plus Letrozole Versus FEC in Women With ER-positive, HER2-negative Breast Cancer, registered on 07/04/2016 and first posted on 18/04/2016, NCT02742051 .


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/etiologia , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Biomarcadores Tumorais , Biópsia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Epirubicina/administração & dosagem , Everolimo/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Projetos Piloto , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Resultado do Tratamento
18.
Eur J Cancer ; 154: 21-29, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34225066

RESUMO

BACKGROUND: Despite endocrine therapy being the mainstay of treatment for hormone receptor positive (HR+)/HER2- metastatic breast cancer, patients at risk of visceral crisis or doubt for endocrine sensitivity are still offered first-line chemotherapy. Maintenance hormonal therapy is generally offered at the discontinuation of chemotherapy. The MAINtenance Afinitor study is a randomised, phase III trial comparing maintenance everolimus combined with aromatase inhibitors (AIs) versus AI monotherapy in patients with disease control after first-line chemotherapy. METHODS: Patients with stable disease, partial response or complete response after first-line chemotherapy were randomised to everolimus plus AIs (exemestane or letrozole or anastrozole) or to AIs alone. Primary aim was progression-free survival (PFS). Secondary aims included response rate, safety and overall survival (OS). RESULTS: In total, 110 patients were randomised to everolimus + AIs (n = 52) or to AIs (n = 58). Median PFS was 11.0 months (95% confidence interval [CI] 8.1-13.8) in the everolimus + AI arm and 7.2 months (95% CI 4.7-10.9) in the AI monotherapy arm (hazard ratio [HR] 0.71, 95% CI 0.47-1.06). Objective response rate was 22.4% in everolimus + AI arm and 19.2% in AI monotherapy arm. A higher proportion of disease progression as best response was reported in the AI monotherapy arm (28.8% versus 14.3%). Median OS was 35.7 months (95% CI 26.0-47.8) in the combination arm versus 33.5 (95% CI 26.4-42.7) in the AI alone arm (HR 1.0, 95% CI 0.61-1.62). CONCLUSIONS: EVE + AIs did not significantly impact on the outcome of metastatic breast cancer patients deemed suitable for first-line chemotherapy. Also taking into account treatment tolerability, maintenance endocrine therapy remains the standard. TRIAL REGISTRATION: EudraCT: 2013-004153-24.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Everolimo/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/mortalidade , Everolimo/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade
19.
Anticancer Res ; 41(7): 3287-3292, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230123

RESUMO

BACKGROUND: Osteosarcoma is the most frequent malignant bone neoplasm. The efficacy of combination therapy of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and a mammalian-target-of-rapamycin (mTOR) inhibitor was previously reported in several cancer types. In the present study, we evaluated the efficacy of a combination of palbociclib (CDK 4/6 inhibitor) and everolimus (mTOR inhibitor) on an osteosarcoma patient-derived orthotopic xenograft (PDOX) mouse model. MATERIALS AND METHODS: osteosarcoma PDOX mouse models were randomized into five treatment groups of seven mice each: Group 1, untreated control; group 2, doxorubicin treatment; group 3, palbociclib treatment; group 4, everolimus treatment; group 5, palbociclib-everolimus combination treatment. Treatment duration was 2 weeks. RESULTS: The palbociclib-everolimus combination reduced the tumor-volume ratio in the osteosarcoma PDOX mouse model compared with the control and doxorubicin (p=0.018). Everolimus alone also inhibited osteosarcoma PDOX growth compared to the control (p=0.04), but less than the combination. Palbociclib alone and doxorubicin were ineffective. There were no significant body-weight losses in any group. Only the palbociclib-everolimus combination induced extensive tumor necrosis observed histopathologically. CONCLUSION: The present study demonstrated that the combination of CDK4/6 and mTOR inhibitors can be a translatable approach for doxorubicin-resistant osteosarcoma in the clinic.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Neoplasias Ósseas/tratamento farmacológico , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Osteossarcoma/tratamento farmacológico , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adolescente , Animais , Neoplasias Ósseas/metabolismo , Modelos Animais de Doenças , Doxorrubicina/farmacologia , Everolimo/farmacologia , Feminino , Humanos , Camundongos , Camundongos Nus , Osteossarcoma/metabolismo , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Piridinas/farmacologia , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
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